Axsome Therapeutics, Inc. (AXSM)

R&D Day 2025

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Jul 21, 2025

All right. Nice. It's working. Good. Good morning, everyone. Thank you all for joining us today. For our Frontiers in Brain Health R&D Day. During today's event, we'll be making certain forward-looking statements regarding, among other things, the efficacy, safety, and intended utilization of our investigational agents, our clinical and non-clinical plans, our plans to present or report additional data, the anticipated conduct and. The source of future clinical trials, regulatory. Plans, future research and development plans, commercial plans, and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions, and expectations of future. Events that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward looking statements. These and other risks are described in. Our periodic filings made with the Securities. Exchange Commission, including our quarterly and annual reports. You are cautioned not to rely on. These forward-looking statements are made. Only as of today's date. Company disclaims any obligation to update such statements. Joining me today are Dr. Herriot Tabuteau, Chief Executive Officer, Mark Jacobson, Chief Operating Officer, Dr. Sue Giordano, Senior Vice President of Medical Affairs, and our distinguished guests. Who will be introduced shortly by Mark Jacobson. We will pause for Q&A. Following each speaker's presentation, with that. I will turn it over to Mark Jacobson. All right, good morning, everyone. Thanks for bearing with us here. We're excited to get started for our Frontiers in Brain Health R&D Day. We're honored to be joined today by six experts, and each is recognized as a leader in their field. It is my pleasure to share with you. You know who those are. Joining us today are Dr. Andrea Chadwick, Dr. Jeffrey Cummings, Dr. Andrew Cutler, and Dr. Susan McElroy. McElroy, Stuart Tepper and Michael Thorpy. Dr. Andrea Chadwick is the Kasumi Arakawa Professor of Anesthesiology, Pain and Perioperative Medicine, and the Director of the Fibromyalgia and Centralized Pain Exploration, or the FACE Lab, at the University of Kansas Medical Center. Dr. Jeffrey Cummings is the Joy Chambers-Grundy Professor of Brain Science, Chair of the Chambers-Grundy Center for Transformative Neuroscience, and Clinical Professor of Neurology at the UNLV Department of Brain Health. Dr. Andrew Cutler is a Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University. Dr. Susan McElroy is a Professor of Psychiatry and Behavioral Neuroscience and the Chief Research Officer and Director of Psychopharmacology Research. At the Lindner Center of HOPE at. The Geisel School of Medicine at Dartmouth. Dr. Stuart Tepper is Vice President. At the Albert Einstein College of Medicine. Headache and Professor of Neurology at. The Geisel School of Medicine at Dartmouth. Finally, Dr. Michael Thorpy is a Professor of Neurology and Director of the Sleep Wake Disorder Center at Montefiore Medical Center at Albert Einstein College of Medicine. So. Just a quick snapshot of today's speakers, and we will pass through as. We advance each section, and here's a quick snapshot of today's agenda. Ari is going to start by. Providing an overview and update for our development pipeline. He will turn it over to our guest speakers. First, Dr. Cummings will provide an overview. Overview of Alzheimer’s disease agitation and discuss. The results of the ADVANCE and ACCORD. Phase 3 trials of AXS-05. Dr. Giordano will then provide an overview of smoking cessation. At that point we'll hold a. Quick break, and then we'll resume. Dr. Cutler, who will provide an overview. Of ADHD, major depressive disorder with excessive. Daytime sleepiness and excessive sleepiness associated with shift work disorder. Dr. Cutler will then discuss the results of the FOCUS and PARADIGM Phase 3. Trials of solriamfetol and ADHD and MDD respectively. It will then go to Dr. McElroy. Who will discuss binge eating disorder and the scientific rationale for solriamfetol in this indication. We will hold another brief break at that time. Dr. Michael Thorpy will discuss narcolepsy and AXS-12, followed by Dr. Andrea Chadwick, who will discuss AXS-14 and fibromyalgia. Finally, Dr. Stuart Tepper will present on the acute treatment of migraine. We'll have closing remarks by Ari Maizel. We do hope that today's event. Will provide you with a comprehensive review of the deep innovation happening at Axsome and that the Axsome team is focused on. Thanks for joining us today, both in person and online. I'll now turn it over to. Ari for his opening remarks. Thank you, Mark. Good morning everyone, and thank you for joining us today. At Axsome, we are defining the future of clinical practice in brain health. We are guided in that endeavor by. Our mission to develop and deliver transformative. Medicines for the hundreds of millions of people impacted by central nervous system conditions. This mission reflects our deep commitment to change the way serious CNS disorders are treated by delivering differentiated, evidence-based innovation. We've built our company around a focus. Strategy advancing novel medicines in areas within neuroscience with high unmet needs and clear strategic fitness where we can transform treatment outcomes for patients and create significant value for shareholders. We work at the intersection of psychiatry and neurology, two therapeutic areas with significant disease burden, limited innovation for new and effective treatment options, and critical gaps for patient care. Our current in-market development portfolio includes 10 indications in psychiatry, depression, Alzheimer's disease. Agitation, smoking cessation, ADHD, and binge eating. Disorder in neurology, obstructive sleep apnea, narcolepsy. Migraine, fibromyalgia, and shift work disorder. Today we'll take you through these areas and discuss how we are delivering innovation to patients living with these debilitating disorders. The theme of today's event, Frontiers in Brain Health, embodies the essence of our work and how we pursue it. We advance these frontiers to benefit patients by focusing on novel mechanisms of action and delivering first in class or best in class medicines. We also apply precision based approaches for underserved conditions, and we do it through a model enabled by clinical development, clinical operations, and regulatory innovation and anchored in our deep expertise in neuroscience. An example of this approach is how we advanced the frontiers in depression, one of the most common and disabling conditions in neuroscience. Our strategy delivered Auvelity, the first and only rapid acting oral and. NMDA receptor antagonist for the treatment of MDD. Auvelity is the first new oral mechanism of action approved in the indication in over 60 years. This FDA breakthrough designated product has now been used to treat 190,000 new patients. It is tracking to an annual run. Rate of over $400 million. In our third full year of launch, we believe Auvelity has the potential to reach at least $1 billion to $3 billion. Dollars in peak sales, and we plan. To continue to advance the frontiers in depression by using a precision targeted approach to develop Sunosi as a potential treatment for major depressive disorder patients who have concomitant excessive daytime sleepiness. If successfully developed, this would be a novel indication. We are currently planning a Phase 3 trial in this indication, which we anticipate to initiate later this year. In this indication alone, we believe Sunosi has the potential to reach at least. One to one and a half billion. Dollars in annual peak sales. We are also advancing the frontiers in Alzheimer's disease. AXS-05 has received FDA Breakthrough Therapy designation for Alzheimer's disease agitation and has the potential to be a first-in-class medicine in this highly prevalent and debilitating disorder. We recently successfully completed three positive registrational trials and are actively preparing for our supplemental NDA submission to the FDA this quarter. In Alzheimer's disease agitation, we see a potential peak sales opportunity of over $1.5 billion. We are also advancing the frontiers in sleep, medicine, and cognition with AXS-12 for the treatment of narcolepsy and Sunosi, which has delivered positive results in cognition. In our SHARP study, AXS-12 is on. Track for NDA submission in the third. Quarter of this year. In the second half of this year, Axsome Therapeutics is further advancing the frontiers in brain health across numerous other indications including migraine, ADHD, fibromyalgia, and smoking cessation, using a winning strategy focused on novel mechanisms to deliver first-in-class or best-in-class treatments. Our strategy now positions us. A deep portfolio comprising three differentiated marketed. Products with a pipeline that has the. Potential to deliver seven new FDA approvals through 2028. Overall, our marketed portfolio and late stage pipeline is positioned to deliver total potential annual peak sales of more than $16 billion. Our issued patents extending to the early 2040s further positions us to deliver significant long term value to patients and shareholders. Today. We are honored to have a panel of distinguished clinical experts and key opinion leaders who will discuss our target indications and review some clinical data generated in these conditions with our product candidates. With that, it is now my pleasure to turn the floor over to Dr. Jeffrey Cummings to discuss Alzheimer’s disease agitation. Dr. Cummings, thank you for joining us today, and please go ahead. Thank you, Ari. Really great to be here. Fun to talk about new products. Could I have the slides? All I see is two pictures of me. Are the slides coming up? Very good. Can you show them on my screen? Maybe we can do it like this. I don't want to waste everyone's time. Good morning. This is really great to be here. I'm talking about agitation in Alzheimer's disease. This is an important indication, as you'll see. Next slide. Alzheimer's disease, of course, starts with plaques and tangles. You know that from all of the activity in lecanemab and donanemab and the monoclonal antibodies. These primary proteins have many downstream consequences. Among them are disturbances of transmitter sources and circuits such that the circuit function is disrupted and either cognitive abnormalities ensue from one set of circuits or behavioral from another set of circuits. Can we modify those circuits in a way that benefits patient behavior? The AXS-05 compound is aimed at dextromethorphan, which as you've heard is an NMDA receptor antagonist and a Sigma 1 agonist, and bupropion. Bupropion is in the combination to inhibit 2D6 in the liver so that adequate levels of dextromethorphan are reached. Next slide. Alzheimer's disease is common. I don't have to tell you that. It's in the news every day. It will increase from its current 7 million individuals with Alzheimer's dementia. By the way, that does not include mild cognitive impairment or people who already have amyloid in the brain but are asymptomatic. This is the more severe end of the disease. In this, agitation is very common. Around 70% or 75% of individuals with Alzheimer's disease will have periods of agitation. It's characterized by verbal aggressiveness, physical aggressiveness, or hyperactivity, as I'll show you in a moment. Next slide. Here are the behaviors that we're talking about. Excessive motor activity behaviors. You see there pacing, rocking, gesturing. Then verbal aggressive behaviors. Yelling, loud voice, using profanity, screaming, shouting. These are the things that are so disruptive to families, right? This is why people are institutionalized. Then physical aggression. Grabbing, shoving, pushing, resisting, tearing, destroying property. These are the things that families can't manage. This is why they make the decision that mom or dad is going to have to go into an institution for more professional care. These three categories, by the way, are the three categories of the International Psychogeriatric Association requirements for the syndromic definition or syndromic diagnosis of agitation in Alzheimer’s disease. Next slide. Here again, you see these same behaviors on the left, but now categorized as they are in the Cohen-Mansfield Agitation Inventory, which has become the go-to primary outcome for trials of agitation in Alzheimer’s disease. You see there are four categories here: physically aggressive, physically non-aggressive, verbally aggressive, and verbally non-aggressive. These map pretty well onto the IPA criteria. You see that each behavior is ranked from 1, which is never, to 7, which is several times an hour. Some of these things can become very frequent. You see that no behaviors is a score of 29. Everybody in this room has a score of 29 at least, because you can’t get a zero. It’s important to think about that because when we think about the change from the total score, it doesn’t go to zero, it goes to 29. We have to think about that. A total score would be 203. Next slide. Some of the consequences of agitation: this is a condition in which there’s acceleration of the disease both to death and to cognitive decline, as I mentioned earlier, and higher risk of institutionalization. If agitation occurs, there’s an increased fall risk. We’ll examine that more closely as we look at the data. Greater health care utilization, of course, medications, institutionalization, increased caregiver burden. You can measure this with quality of life measures or other kinds of caregiver distress measures. Greater concomitant medication use, of course, including antipsychotics and poor quality of life for both the patient and the caregiver. Next slide. This is a market that can really be developed, there’s no question about that. The current common pharmacology is the off-label use of antipsychotics. Risperidone, haloperidol, quetiapine are the most commonly used medications right now. There is some use of the anticonvulsants like valproate or carbamazepine and then there’s some use of benzodiazepines. There has been a lot of attention to why not to use those medications. These drugs produce sedation, they can produce falls, they have a black box warning. The antipsychotics do for early mortality, for mortality and they have modest efficacy. There's only one FDA approved medication, this is Rexulti for agitation in Alzheimer's disease. This is a field that I think has a lot of potential for growth in terms of medications. Next slide. There are four trials in the Axsome portfolio for agitation in Alzheimer's disease: ADVANCE-1 and ADVANCE-2, ACCORD-1 and ACCORD-2. Three of these trials, as Ari mentioned, are positive, one is negative. I'll go through these. ADVANCE-1, this is a randomized parallel design. You see there's a single dose, patients were treated for five weeks and the primary outcome was the CMAI. This was statistically significant. ADVANCE-2 was exactly the same design, somewhat larger trial, it was a negative trial. There was a trend towards benefit at every time point in measurement, but the drug-placebo difference was not significant at the end of the trial. ACCORD-1 is a randomized discontinuation design. These are designs where all patients are treated and then at the end of eight weeks of treatment, one group is withdrawn randomly and the other group is continued on treatment and you measure the time to relapse. ACCORD-2 was exactly the same design. Both of these were statistically significantly positive. Now thinking about this portfolio, I like this a lot because I like the combination of the parallel design and the randomized withdrawal. The parallel design gives you the drug-placebo difference in the straightforward way that you're used to. The randomized withdrawal designs give you the enduring effect and I think that's very important as we think about these drugs. How long does the effect last? Four trials, one negative. I would say that's exactly what you expect in a condition that has a very robust placebo response. This is very common in depression trials to have negative trials. It's common in pain, migraine to have negative trials. This is not unusual to have one trial out of four being negative. Next slide. Here you see ADVANCE-1. This was robustly, statistically significant. I'll call attention to a few things in this graph. One is that you see that the efficacy and drug-placebo difference is evident at week two, continues at week three, and is present at the end of the trial at week five. There's a rapid and substantive decrease in agitation, a greater number of patients. A clinical response of greater than 30% was observed in the treatment group compared to the placebo group. As I'll show you in a moment, the tolerability and safety were. This is what the response looks like in terms of the parallel design. Next slide. If we look at the drug placebo differences at each week, week two, week three, and week five, these were again, the statistically significant measures. You see that there is a very robust placebo response. We actually think this is a clinical trial response, not a placebo response, because when a patient gets into a trial, their family has to form, sign informed consent. There's a lot of involvement of the family, a lot of attention from researchers. You get to see your doctor often, and all of that has a very beneficial effect on behavior. We think this is a trial effect as much as it is a placebo response. It is very common in all of these trials of agitation agents in Alzheimer's disease. Let's look at the safety on the next slide. You see the treatment-emergent adverse events were greater in the Axsome group. There were actually fewer serious AEs in the Axsome group compared to the placebo group. There were no deaths in the Axsome group. This is important because the mortality signal in the antipsychotics has been, of course, a source of concern. If we look at individual AEs that occurred in more than 3%, you see somnolence in 8% compared to 3%, dizziness in 6% compared to 3%. Diarrhea, exactly the same, and headache, 3.8% compared to 2.5%. These are low rates of adverse events and manageable. Next slide. Here's the ADVANCE-2. I told you this was a negative trial. I think the importance here is that the difference between this trial and the one I just showed you is the performance of the placebo group. In the last trial, ADVANCE-1, the placebo decline was about 10 points, and there was a significant drug placebo difference. You see in this trial, ADVANCE-2, the placebo decline is about 12 points. That's a substantial amount of the benefit that we saw with AXS-05 in the ADVANCE-1 trial. You see that there again is a trend towards benefit from active treatment at every time point measured, but it does not reach statistical significance at the end of the trial. Next slide. Again, the safety looks pretty good. There's overall a lower incidence of treatment-emergent adverse events. There were only two serious adverse events, very few discontinuations, and again no deaths. Dizziness again is seen. This is the one thing that stands out to me in terms of looking at the AXS-05 group compared to the placebo group. It's been seen when dextromethorphan is used in other circumstances. Next slide. Here's your first look at a randomized discontinuation design. I'm showing you the second half of the trial to begin with because that's the blinded half. I'll just review the structure of these trials. Every patient, when they come into the trial, is assigned to active therapy. That is the open-label portion. You watch the patients for eight weeks, and those that have responded to treatment are randomized to either placebo or continuing active treatment. The outcome is time to relapse from that randomization. I like this design as a trialist because you get to put every patient on treatment when they come in. That's what families want. This is an easier trial to do as well as a very informative trial. The measurement of the enduring response is very important here. What you see is a significantly delayed time to relapse reach statistical significance. You see it mapped there. The difference really becomes evident by about 15 weeks. By 15 weeks is when the placebo group is starting to relapse in a significant way. Of course, not all patients relapse. You also see that it's 3.6 times less likely to relapse if they're on AXS-05 compared to placebo. Keep an eye on that number because I'm going to show it to you again. Let's go to the next slide. Here's another way of looking at these data. That is, what was the % of people who relapsed. Now, not looking at the time to relapse, but the % of people who relapsed in the observation period. You see that the relapse rate on AXS-05 was 7.5% and the relapse rate on placebo was 25.9%. A very important and robustly significant difference. Next slide. Now, I'm showing you the first phase of these trials. This is the open-label phase. Patients come in, they are all put on drug, and then they are observed for eight weeks and then they're randomized to either drug or placebo to watch the withdrawal. What is the response during treatment? Here in the active treatment portion of the trial, you see a steady increase from 22% response at week one to 93% response by the end of the second month. Again, a very robust response and continuing improvement in the response in terms of treatment with AXS-05. Again, all these patients are on AXS-05, none are on placebo. Next slide. Let's look at the safety here. Again, you see a very similar overall incidence of treatment-emergent adverse events. You see one serious adverse event in the Axsome group and two in the placebo group. You see no discontinuations due to TEAEs and no deaths. There's diarrhea about twice as common in the AXS-05 group compared to placebo. There were four falls in the AXS-05 group compared to the placebo group. There was unexplained back pain in three patients in AXS-05 and two in placebo. Next slide. Now let's look at ACCORD-2. This is the second randomized discontinuation trial in the four trials that we are reviewing today. You see that there was a significant delay in relapse in the AXS-05 group compared to the placebo group. Kind of interesting to me is it was the patients were 3.6 times less likely to relapse compared to placebo. That's exactly the same number we saw in ACCORD-1. You get the mapping there. Little bit different distribution of the relapse in the placebo group. As we look at it, there were still relapses occurring as late as Week 16, 17, 18 in this particular group. There was more or less continuous increasing relapse in the placebo group and controlled relapse in the active treatment group. Next slide. We'd like to look at the % relapse as well as the time to relapse. The primary outcome, which was statistically significant, is the time to relapse. That's the FDA's preference difference. The % of relapse is also important. Here you see in the AXS-05 group, 8.4% relapse in active treatment and 28.6% in the placebo group. Substantially more relapse in the observational period compared to active treatment. Next slide. Now, here's the open period of the ACCORD-2 trials. All patients are put on medications for the first weeks of the trial. You see that week one is 47%, a little bit more than we saw in ACCORD-1, and month two, which is important to me, is the randomization period. There was a 71% response rate at the time of randomization. Very important and progressive response to treatment. Next slide. I've only shown you the primaries so far, which was the CAMI and ADVANCE-1 and ADVANCE-2 and time to relapse in ACCORD-1 and ACCORD-2. Now, in this slide, I'm showing you the secondary, which is the CGI. That's the Clinical Global Impression severity. I like this slide a lot because it's what doctors do. When the patient comes in and the daughter is accompanying the demented mother, what does the doctor say? She says, how is she doing? That's a global response. That's a global question, and you get a global response. It's much more like what happens in the clinic than the CAMI is. No doctor has time to do the CAMI, but they do the global. They want to find out globally is the patient better or not. You can see this again is from ACCORD-2. You see that in the CGI-S response rate, it was statistically significant in terms of time to response. That is the graph on the left, and the graph on the right is the % of responders as measured by the CGI-S. You see that in terms of patients who relapsed, it was 13.3% on AXS-05 and 39% on the placebo. If anything, the clinician who's doing the global sees a little bit more than the clinician who's doing the CAMI. I like the CGI-S a lot. ACCORD-2, safety. Let's go on to safety. There's nothing new here. The overall number of TEAEs is about the same. You see serious TEAEs more common in placebo than AXS-05. No discontinuations in the AXS-05 group, and of course, no deaths. If we look at the specific TEAEs, you see anemia, which we didn't see in any of the other trials. Headache, 3.7% compared to 2.4%. We saw that before. Hyperkalemia, again, we didn't see that in any other trials. Somnolence, we occasionally see that. We saw that in ADVANCE-1, and back pain, which we saw in ACCORD-2. Overall, this is a very manageable safety and tolerability profile. Nothing has emerged that would be a showstopper in terms of safety. Next slide. If we look overall now at all 456 patients who have participated in the AXS-05 trial portfolio, you see that overall TEAEs in around 40% of patients. That's common. You see it in the placebo group as well. Very low rate of serious TEAEs, 2.6%. Discontinuation also low and no deaths. I'll just emphasize that because it's in contrast to our worry that we have with the antipsychotics. Headache was observed across several of the trials. Overall, 5%, 5.5%, diarrhea, postural dizziness, falls, hyperkalemia, somnolence, and urinary tract infection in some of the trials. Those were observed in some trials and not in other trials. I would say that dizziness and headache are the two things that one might expect to see in patients who receive treatment with AXS-05. Next slide. Let's just summarize before we go to questions. There have been four Phase 3 clinical trials looking at efficacy. I like this distribution of the trials because you get to see both the acute effect and its onset in the parallel design, and you get to see the enduring effect in the randomized discontinuation design. You see that three of the four trials were robustly, statistically significant on the primary outcome. That was the CAMI in ADVANCE-1 and ADVANCE-2, and the time to relapse in ACCORD-1 and ACCORD-2. I'll just emphasize it's not unusual when you have situations with this robust placebo response to have a negative trial. Next slide. Overall, we'd say there's a low discontinuation rate, it's less than 2%. People stay on the medication. Of course, if you're getting relief, you want to stay on the medication. No deaths have been reported. This contrasts with a worry that we have with the antipsychotics. I might draw attention to the fact, by the way, that there was no decrease in cognition, which was also observed in some trials of antipsychotic settings not associated with common AEs. There were a few falls, there were few fusidation and dizziness, but overall very low rate. There was consistent long-term safety in terms of these observations. Next slide. This is my final slide, just to try to put this into some context and some takeaways. Agitation is really highly prevalent. It occurs in about 70% of patients with Alzheimer's dementia. I would say that not all of those patients have severe enough agitation to require treatment, but many of them do. Treatment is an unmet need in Alzheimer's disease because we have so few alternatives. As a matter of fact, we have only one approved alternative and it has some disadvantages. Auvelity is a novel NMDA antagonist and Sigma-1 agonist that affects transmitters that appear to be important in terms of the mediation of agitation through circuitry in the brain. This drug has demonstrated robust and rapid efficacy in terms of onset of the therapeutic response and in terms of the enduring therapeutic response. It was not associated with death, cognitive decline, meaningful sedation, or marked increased risk of falls in long-term trials. I will stop there and I'm very happy to take a few questions. I think we're already at the limit of our time, so I'll let our host decide how you want to manage the time. Testing. Okay, thank you, Dr. Cummings. We have a few minutes to take some questions from the room. We have a few mics going around. I can see at least one hand up here. I have a little view of the room. Hi there. Thank you for the presentation. This is Joe Thome from TD Cowen. Maybe can you talk a little bit. About your clinical experience with Rexulti in your practice? If Auvelity is approved for the indication, how would you consider using it. One therapy versus the other in your patients? Really good question. Of course, we'll see how this plays out in the market if AXS-05 is approved. I think docs and healthcare systems are worried about the black box warning and the content of the black box warning, which is mortality. In general, when patients become agitated, they'll be agitated frequently for two or three years. Let's say that they're moderately demented and they will continue to be agitated for several years. The risk of death goes up with longer exposure. I think there will be a preference for use of AXS-05 over Auvelity for safety reasons. That's how I think it'll play out because I think healthcare insurers are very sensitive to liability issues, and the efficacy looks pretty similar to me. The trials are different. You can't compare them trial per trial, but the efficacy looks very similar. I think the advantage of AXS-05 would actually be in the safety. Hi, Jun Lee from True Securities. How does the AXS-05's efficacy compare in your opinion from off-label SSRIs? SSRIs. Fourth treatment of agitation? Is that what you're asking? Yes. The citalopram trial was so interesting. Interesting because this was an SSRI which did show a statistically significant reduction in agitation. The reason that it never caught on is because the dose that was used was reviewed by the FDA and it was decided that that dose was too high in older individuals. It produced cardiac abnormalities. The FDA recommended against the dose that worked in the trial and only one dose was tested in the trial. From there the Hopkins group, which did a terrific job with this trial, went on to test escitalopram and the escitalopram study showed no drug placebo difference. That trial was executed during the pandemic and I am not sure that those data are securely negative. We have only one trial showing SSRI efficacy in agitation and it's at a dose that we just wouldn't use in older individuals. The database for SSRIs is too thin at this point to represent a meaningful alternative. Just a quick follow up question. Our understanding is that a lot of Alzheimer's patients also suffer from depression. Do you have any anecdotal evidence of use of Auvelity in that? Depressed Alzheimer's patients with benefit and agitation as well. Thank you. You know, I think it's a possibility. I personally don't have any experience with that. My use with it has been low because I don't see that much major depression in Alzheimer's disease. They certainly have mood changes and they can be sad. Do you see the whole repertoire of symptoms that one sees in major depressive disorder? You don't, and so I don't. You tend not to use antidepressants in them. I think it's a pathway that's really interesting in this case and there might be some additional benefit, but I think we just don't know that yet. Hi Dr. Cummings, thanks for taking my question. Tanish Nakanj from RBC. Maybe from your standpoint, if you. Could you help us reconcile the differences in? Responsivity at month two for ACCORD-1 and ACCORD-2, what that means from a clinical standpoint, the 93% response versus a 71% response. Thanks. I can't give you a definitive answer to that, except to say that these response rates vary somewhat from trial to trial. They are so dependent on the population that is recruited and then the clinical trial sites and how they're measuring. A difference like that is not a surprise to me, nor do I have a specific explanation for it. Thank you. Hey, Matt Hershenhorn from Oppenheimer, thank you so much for hosting us and Dr. Cummings, really appreciate your perspective. One question for you. Just as you see the launch of Leqembi and Kisunla, the A beta antibodies and increased awareness generally for treatment options now for Alzheimer's, do you expect that to benefit awareness for symptomatic treatments like Auvelity as well? Can you share any thoughts on how you see clinical practice for AD evolving, especially considering scenarios where patients may be on both the A beta antibodies and symptomatic treatments like Auvelity? How do you plan to manage those patients, especially considering safety? Really great questions. The monoclonals I think are really important because they show we can do something to this disease at the biological level. I love them for that. There has been relatively slow uptake of these. These are complicated drugs to use. As you know, they're given intravenously. They have to be monitored in the early part of the administration period for ARIA with serial MRIs. These are complicated to use and not all neurologists are really comfortable with this yet. There is going to be slow, regular increase in these where the drugs are already getting better and better and there will soon, I think, be subcutaneous administration available. These drugs are going to be in the market and many more patients are going to be on them and they're going to need treatment with symptomatic agents. All of the trials already allow symptomatic cognitive enhancers. Most of the patients are on a cholinesterase inhibitor and some of them are on memantine. If a patient has an agitated episode, and they're very likely to happen maybe for longer periods of time if the disease is slowed by the monoclonal antibodies, they're going to need treatment. There will be patients who, many patients I think, who are on different combinations of drugs including anti-agitation agents as well as the anti-amyloid monoclonals. The monoclonals have only two major adverse events, ARIA and infusion reactions, because you're dealing with a monoclonal. It has a very specific target in the brain. There is no overlap between the adverse events that are seen in the monoclonals and the adverse events that are seen in symptomatic agents such as AXS-05. I'm not really worried about it and it's absolutely going to happen and we absolutely need those drugs. I think we have time for a couple more questions in the room. Hi, Jason Gerberry from Bank of America. Thanks Dr. Cummings. What is your question? The patient profile of who you think would make sense to start treatment with AXS-05? Is it someone with more milder agitation? Would you want to wait till. They're more moderate in their symptoms? Part of the reason why I'm asking this, you talked about the safety profile of AXS-05. I'm wondering if you're comfortable treating the majority of your Alzheimer's patients, presumably most of them have some sort of mild agitation. Secondarily to that, what we've heard about the Sunosi launch is. That like in the long-term care. Facility or the nursing home, reimbursement constraints are more challenging. From a commercial standpoint, getting to. The patient in the outpatient setting before. They're put in a nursing home, may. Have some more favorable, advantageous payer considerations. Wonder if you can comment on that as well. Thanks. Yeah. In order to come into these trials and to be randomized in the advanced trials, one, they had to have a neuropsychiatric inventory score of 4 or more. That means that the agitation was not very severe at baseline, but it was severe enough that the family is complaining and the doctor feels obligated to use a medication because nonpharmacologic mechanisms, talking to the patient more nicely, making sure that their day is regularized, trying to distract them when they get upset about something. When those things don't work, you need a drug like AXS-05 and that will be the population. It's patients who have more than mild agitation. Families can usually manage mild agitation and they don't really want their loved one on drugs most of the time. When it gets up to moderate, they want a drug, they want relief from this because it's just too much of a challenge for them. I think the patient is going to be an elderly woman. Many more women with Alzheimer's disease than men who is moderately agitated and there aren't really contraindications to the use of these drugs. I suppose if you were on another 2D6 inhibitor, you might worry about that, but this is going to be an easy drug to use in the market. I wouldn't be waiting for more severe agitation, but I would be waiting for moderate agitation. I want to make sure that the patient needs treatment before I offer them treatment. Hey, Miles. Mentor from William Blair. The question is just on the minimally clinically important difference on the current Mansfield agitation versus placebo and whether that's been established or not. I think if you look at the 29 items there, some of them are biting, punching, pretty severe, and others are pacing and maybe eating the wrong meal. Drinking the wrong drink, which can. Be interpreted as varying degrees of severe, I suppose. Any color on that would be. Really helpful as it relates to access. Or AXS-05 placebo seen in ADVANCE-1. Thanks. Yes. Thank you for your question. The MCID has been a hot topic, hasn't it, in terms of Alzheimer's disease research? I regard the MCID as a within-patient measure, not as an outcome in a clinical trial. The FDA has no standard for the MCID as an outcome for a clinical trial. It is a within-patient measure. I am not aware of the MCID for the Cohen-Mansfield. The way I would approach it would be either a clinician or a family grading of what is mild, moderate, and severe agitation. I would map that onto the KAMI, and then I would use that for a patient who is a patient failure. You could tell the number of patients who did not respond by the number who develop from some baseline a more severe deterioration on the KAMI. It works well as a within-patient measure. People have tried to apply it as a clinical trial outcome, and it's way too severe. Very few trials would actually stand up to the MCID because of the way it's done. I would see it as a very useful measure in terms of the worsening of the patient and the number of patients who were non-responders. That's how I would use it in the agitation situation. Dr. Cummings, thank you so much for the presentation. This is Yatin Suneja from Guggenheim. You seem to like the. Distribution of studies right between the randomized. Control because they give a different answer in the randomized placebo study. I'm curious to hear from you. Do you have a read on how? regulators look at these two specific formats of studies? Do they have a preference for one versus the other? What about your colleagues when they. Are looking for treatment or when they're evaluating drugs, what type of studies or format they. Prefer or they like. Thank you. Yes, good question. I'll just point out that the randomized discontinuation was recently used in the Acadia trial for dementia-related psychosis. Although it didn't lead to an approval for various very complicated reasons with the FDA, it was an excellent example of a randomized discontinuation trial in psychosis of individuals with neurological disease and psychotic phenomena. We're seeing more and more of this, and I think the regulators almost always want to see a double-blind parallel comparison design because that's the standard. I am also under the impression, and you have to ask Teresa about this, that they like the additional information which accrues from using randomized discontinuation because the enduring nature of the response is very important. I think it's important, particularly in these drugs that are used in a nursing home setting, because the nursing homes are under great pressure to get patients off of psychotropics. The gold star rating is to get patients off of psychotropics. If you know the relapse rate, you're in a position to discuss whether patients should be taken off of medications or not. I like the additional information that comes off. I think you wouldn't want to take a package that was only randomized discontinuation to the regulatory authorities. The balance between a parallel design and a randomized discontinuation design is a strong portfolio. Dr. Cummings, thank you very much. joining us today and for your insights. I'm pleased to now turn the floor. Over to Dr. Sue Giordano, Senior Vice President. President of Medical Affairs at Axsome. Hi everybody. Thank you. Thank you, Ashley. And thank you, Dr. Cummings, for that informative review of the data for AXS-05 and Alzheimer’s disease agitation. I’m going to provide another area where we think AXS-05 has a scientific rationale for treatment. Of course, there are multiple areas where we think this is the case. We have major depressive disorder for Auvelity, where it is helpful in adults. For major depressive disorder, we just heard really compelling data, I think, in Alzheimer’s disease agitation. I’m going to be talking about another area where I think there’s promise and that’s smoking cessation. I’ll provide a little overview on the unmet need that’s still available there for smoking cessation and then a little bit of the rationale, scientific rationale, and end up with some preclinical data before lunch. Slide one, please. Thank you. There still remains a really high unmet need in smoking for smoking cessation. Smoking-related diseases affect millions of people in the U.S. and, of course, globally. It remains the number one preventable cause of death in the U.S. In addition to this high human cost and suffering, there is a huge and staggering economic toll because of smoking and the diseases related to smoking. Next slide, please. Thank you. We're learning a lot more about how smoking affects different body functions and systems. We've learned a lot even in the last 10 years. We know, of course, and everyone knows and is familiar with some of the top two, lung cancer and COPD. We've learned that there's effects in multiple systems, cardiovascular system and even in the immune system in lowering immune efficiency and also in other cancers besides lung cancer. This results in a really high impact and increase in mortality and actually a 10-year loss of life for people who smoke compared to non-smoke. Next slide. Smokers are well aware of these consequences and they want to quit. 70% of smokers at any given time will say that they want to quit, but it's really hard to quit. The statistics on quitting without any intervention are very, very low. Even with the current treatments available, of which there are three FDA, it still remains less than 20% success rate for abstinence from smoking after a year, which really identifies the need and speaks to the need, I think, of new treatments that are safe and tolerable and efficacious in this population so that we can help people who want to quit and quit smoking. The need is even greater in mental health. Many patients who have serious mental illness smoke and the success rates for quitting in that population are even lower. Okay, thank you. Next slide, please. Please, Ashley. Thank you. Smoking affects the nicotinic receptors, and nicotine binds to nicotinic acetylcholine receptors. It causes influx of certain neurotransmitters, including dopamine, which is reinforcing, others, norepinephrine and other neurotransmitters, and is reinforcing behavior. In addition, it also causes withdrawal symptoms. When you take smoking away, you get withdrawal symptoms that are unpleasant, like agitation and anxiety. AXS-05's mechanism addresses many of these mechanisms of nicotine dependence. First of all, NMDA receptor antagonists and nACh receptors have been implicated in the mechanisms for smoking dependence and nicotine addiction. In addition, dextromethorphan is also a Sigma-1 agonist, as we heard, and that is also implicated in smoking dependence and nicotine dependence and may affect tolerance to withdrawal symptoms. In addition, of course, there's also the bupropion, which is there, which increases dopamine and norepinephrine we know has an effect on smoking cessation. Both dextromethorphan and bupropion also bind to nicotinic acetylcholine, certain nicotinic acetylcholine receptors. There's a good. Rationale for why we think AXS-05 will be helpful in this population and help patients quit smoking. In addition to this mechanistic data, there's also some preclinical. We have some really nice preclinical data in rats and another reason to believe dextromethorphan really reduces the nicotine administration in nicotine-addicted rats. The rats are addicted to nicotine, they're allowed to self-administer nicotine, and dextromethorphan in a dose-dependent way decreases the administration of nicotine in rats. Rats metabolize dextromethorphan a little different than humans. Of course, we have the bupropion and that inhibition mechanism that allows for the increase in dextromethorphan in humans. This provides, I think, really good rationale along with the scientific mechanism for why we think AXS-05 will be useful in smoking cessation and provide another option for people who want to quit. On the final slide, just to finish up. Yeah, thank you. This lays out the rationale that we just talked about. Not only the NMDA receptor, dextromethorphan and sigma 1 and NMDA bupropion, but also the clinical data, preclinical data. Okay, next and last slide. Is that it? Okay. All right. Thank you. To finish up, we really think with this data and this information that AXS-05 is going to be promising in smoking cessation. We're really excited to get started on the clinical program this year. Thank you very much and I will turn it over back to Ashley. Thank you. All right. Thank you, everyone. We'll actually now be breaking for lunch, and we'll resume in about 15 minutes. Thank you. I can't believe I forgot your name. Oh baby, won't you come again? She said I've got a problem with your shoes and your CH things. Might move in, and I thought that you were straight. Now I'm wondering, you. Stop, Conceited. I said I love you. What does it matter if I lie? I don't regret it, but I'm glad, so don't you tell me. You just don't get it, 'cause I know you and I always know the sound of your heart. It'S. Not about reciprocation, it's just all about me. Sycophantic, prophetic, Socratic junk, you wannabe, and there's so much skin to see. It's simple as a pecun philosophy, oh. When you say I'm such a cliché, I can't see the difference. Any evil way, we left things to protect my. Mental health, but you call me when you fall and you playing yourself, you. I said I don't love you. What does it matter if I. I don't regret it, but I'm glad we recruit, so don't. You tell me that you just don't. Get it. When I know when you're around, 'cause you know the sound. I know the sound in your heart when. I know. Put them back up on the shelf. Kiss my little baby girl. Isn't me, then I come and I left you. I'm a rebel just for kickstart. I've been feeling it. Since 1966, now might be over now. I feel it still. I'm a rebel just for kickstarter. Let me. Kick it like it's 1986 might be. Over now, but I feel it still. Got another mouth to feed. Leaving with the babies here. Mama called a grave digger. Gone with the fallen leaves. Mama come without a lefty. Ooh, I'm a rebel just for kicks. I've been feeling. It's since 1966 now that I had, you still feel it, still give to. That easy living goodbye to my hopes and dreams. Stop flipping for my enemies. We could wait until the walls. Stumbling little to the kids in the mid. Is it coming? Is it coming? Is it coming? Is it coming? Is it coming back? I'm a rebel just for kicks, yeah, your lovers and a for my heart to eclipse now. Might be over now. I feel it still. There's a. Boy, I know he's the one. Dream of. Looks into my eyes. Takes. Me to the clouds above. Can't seem to get enough. When I wake from dreaming, tell me is it really love? How will I know? Just your feelings, how will I know? How will I know? How will I know? How will I know if he really loves me? I say pray with every heartbeat. I fall in love whenever we meet. I'm asking you cuz you know about these things. How will I know? How will I know? Oh, wake me, I'm shaking. I wish I had you near me now. Said there's no mistaking what I'm feeling. Really love, tell me how will I know? How will I know? How will I know? How will I know? How will I know if he really loves me? I say a prayer with every heartbeat. I wanna love whenever we meet. I'm asking you cuz you know about these things. How will I know? How will I know? How will I know? How will I know if he loves me. If he loves me not. If. He loves me, if he loves me not, if he loves me, if he loves me not. Oh, I will not. How will I know if he really love? Told her I had to go, and I know it ain't pretty when her. Heart get broke, leaving to find my. Told her I had to go, and I know it ain't pretty when. Two hearts get broke, yeah, I know. It ain't pretty when two hearts get broken. Someday we sit down together and laugh with each other. I won't fall. Cigarettes in the ashtray, reminiscing on those past days. I thought you don't know my last name, but that changed and I traveled around the world. Think where you living at now? I heard you moved to Austin, got an apartment and settled down. Every once in a while I start texting, write a paragraph, but then I delete the message. Think about you like a pastime. I could cry you a river, get you baptized. Oh, I wasn't ready to act right. Used to always think I'd get you back right. They say that things fall apart, we were going to. Move to Brooklyn, you were going to study. Art, like, is just a tool to remind us who we are and that we are not alone when we're walking. In the dark. I'm on a mission. I. Present, my bright but emotions won't grow. Changing our way, love is never. Again. Why is your bedroom so turned away? On your own side? It's my timing. The floor I respect. is so dry, yet there's still messages. Of you. Love love. Again love. It tastes in my house. Desperation stays. Home, just something so cold just can't. You are again love. It. When I wake up in the morning, love. And. The sunlight hurts my eyes. Something without. One morning love bears heavy on my. Mind. I look at you and. The world's all right with me. Just. One look at you and I know it's going to be a lovely. Seemed. Impossible to fade. When someone else instead. Of me. Always seems to know the. I look at you and the world's all right with me. Just. One look at you and I know it's going to be. When the dead lies ahead of me, seemed impossible to fail, and when someone else instead of me. Always seems to. I look at. You. The world's all right with. Me. I just want to look at. You. I know it's going to dad. Oh, baby. It's out of my control, it's going home. You're just a chance I take to keep on dreaming, you're just another day. That keeps me breathing. Baby Mushroom. Sa. You're bringing me closer to the edge of letting go? You're just a hideaway, you're just. A feeling you let my heart escape beyond the meaning, pulling my head into the clouds. I'm floating home when you. Get me going. I can't find a. Way to stop. Just a chance I take to keep on dreaming. Just another. Day that keeps me breathing. I'm holding. It back just want to say more, but you're just a hide away. You're just a feeling. You let my heart. Escape beyond the meaning I can find. A way to stop. Oh, maybe it's out if I control what's going on. You're just a chance I take. Just keep on dreaming just enough, the day that keeps me breathing. All right, welcome back, everyone. We hope you had a chance to grab some food. We're going to keep things moving here with our next session as you continue. To enjoy your meal. I'm pleased to turn the floor. Over to Dr. Andrew Cutler, and he'll be providing an overview of Sunosi in ADHD, MDD with excessive daytime sleepiness. In shift work disorder, thank you. All right. It's always a little intimidating to be standing in front of a large picture of yourself, but that actually was a pretty good hair day, so I'm comfortable with that. I'm really happy to be here to talk about a couple of topics near and dear to my heart. I've been doing clinical trials for 30 years, psychopharmacology trials, partnering with pharmaceutical companies to try to get new medications approved to help more of our patients. It's been a privilege working with Axsome Therapeutics for quite some time from even before Auvelity was FDA approved. I was an investigator on some of the trials. Sunosi is an old friend as well. I actually was consulting with Jazz Pharmaceuticals when they had it in development. Let's talk about Sunosi from a neurobiologic point of view and confession. My research training is dopamine receptor pharmacology. I find this probably way too interesting. I'll try to not get too excited. I was very impressed with the questions that came up earlier. Having presented to investor groups before, I know some of you are quite sophisticated. What we have here is the putative mechanism of action of Sunosi. Sunosi is known to be a potent dopamine, norepinephrine reuptake inhibitor, which of course predicts many positive actions in the brain and positive effects for many psychiatric conditions. In addition, it has also been found to be an agonist at the TAR1 receptor. TAR stands for trace amine-associated receptor. This receptor system was not even known about until the late 1990s. This is a much more recently discovered system. We've always known trace amines are in the brain, but we thought they weren't doing a whole lot. It turns out they're doing a whole lot. They have receptors and they do a lot. What TAR1 agonism does is it modulates monoamines and glutamate. It's kind of a modulator, which is a nice thing. It's good in the brain to not just simply have too much or too little, but to try to modulate a little bit. What we have here is an example of the different projections that are going on. Our monoamine cell bodies live in the brain stem, which is the midbrain. You see the locus coeruleus in the middle of that picture is where norepinephrine cell bodies start, and then they project up to various other structures in the brain. Next to that, we have the substantia nigra and the ventral tegmental area, VTA. Those are the dopamine cell bodies projections. Now, dopamine and norepinephrine are very involved with a number of important functions when we're talking about ADHD and depression. They include cognition, attention, alertness, also mood, and also modulation of motivation reward systems. Both ADHD and depression are as much dysregulation of arousal and motivation reward as they are of mood. Having these kinds of effects predicts that there would be some positive activity. As you can see at the bottom here, it's quite multimodal and especially this TAR1 to me is quite a differentiator. This distinguisher, some people look at this and say, isn't that how bupropion works? Yes and no. Bupropion is actually an NDRI. It has more affinity for the norepinephrine transporter and it's not nearly as potent at those transporters as solriamfetol is. Solriamfetol is a DNRI with higher potency. Okay. Let's talk about ADHD first. I just want to say a global comment here. ADHD is a real medical condition. It is common, it is highly genetic, and it is very treatable. Treatment makes a huge difference. This is not a condition where people are just a little spacey and forgetful. Isn't that cute? No, this is a neurobiologic condition that you can actually see differences in structure and function of the brain. It's a condition associated with significant medical comorbidity and premature death. Believe it or not, as I'm going to go into, treatment has been shown to improve all of those parameters, including the effects on somebody's life. This to me is the call to action and the reason to believe. Very common. We think that the incidence actually approaches 10% of the population. Now, when I first trained, shows you how old I am, there was no such thing as adult ADHD. Literally, we were taught it was a childhood disorder that you outgrow. Yet it is highly genetic, and it's a neurobiologic wiring disorder. There's no such example in all of clinical medicine of something like that that just goes away. Our brain develops and changes, our compensatory skills change, and this is probably why it was missed, if you will, for many years. More recent studies, longitudinal studies, have shown a very high rate of persisting into adulthood. More and more, we're now recognizing and diagnosing. The fastest growing group of people being diagnosed and treated are actually adult women. Right now. As you know, we divided into inattention and hyperactive impulsive behaviors. There's significant associated features as well, including emotional dysregulation and mood problems. As I said, arousal, circadian rhythm, sleep, motivation, reward. You heard about the association with smoking, also substance abuse and significant impairment in really every phase of life. Now I'm going to tell you two quick stories about two patients of mine at different ends of the age spectrum to illustrate what we're talking about here. I'll never forget a few years ago I had a seven-year-old boy that I was treating. Mom comes in crying and of course I'm a parent. I'm like, oh my God, I don't want to hurt a kid. Is everything okay? She said, he finally got invited to a birthday party. Think about what that means in a kid's life, right? A seven-year-old kid. Before that he couldn't get along with peers. All right, flash to another age. I diagnosed a 71-year-old gentleman, a retired lawyer with ADHD, and he cried. He said, you mean my life could have been different all this time? I said, yes, but you know what, you've got more life ahead of you. Let's make it even better. That just illustrates to me that this is a lifelong disorder. ADHD is associated with increased premature mortality. This is brand new information published in January of this year. It's called the Onions Study out of the UK. What it shows is that if you have ADHD, if you're a man, you die on average seven years earlier than if you don't have ADHD. If you're a woman, it's even worse. You die nine years earlier, which is counterintuitive because women tend to live longer than men. There are two categories of reasons for premature mortality. There are unnatural causes, and that includes suicide and accidents. There are natural causes which include cardiovascular disease and diabetes. The single highest genetic linkage, and yes, I'm raising my voice because it's important, the single highest, and this after lunch, I gotta wake you up, the single highest genetic linkage with ADHD I would have thought would be depression or anxiety, which are the most common psych comorbidities. No, it's obesity. It is being overweight and that may be from dysregulation of your motivation, reward system and circadian rhythm and so on. Obviously increased chance of getting arrested, not graduating high school, being underemployed, maintaining relationships, you're way more likely to be divorced. Sexually transmitted diseases and unwanted pregnancies and motor vehicle accidents and treatment in particular has been shown to improve many of these different aspects, including there are some interesting driving studies that showed that. All right. Yet, even though we have all this evidence of this being a real medical condition with significant consequences, it is still underdiagnosed and undertreated. I think because there's such stigma here and there's such underestimation, like I said, people underestimate. Oh, you're spacey, you're forgetful, whatever. The newest research on persistence into adulthood is quite surprising. A friend of mine, Maggie Sibley, and colleague followed patients over a period of years. What she found was that no, over 90% of the time it persists into adulthood, but it often waxes and wanes depending on the environment and stressors. The most recent data before that was 50% to 60% persistence, but that was based on something called point prevalence. If I look at one point in time. Over time what happens is adults can compensate, but you can't go through life without stressors and things changing and losses. When those things happen with ADHD, that's when the wheels can fall off. If you think about our society, it has become increasingly cognitively loaded, if you will. The jobs now depend much more on your cognitive ability, paying attention, remembering things, being organized, especially with AI. Now we're going to be going. That is a real challenge for people with ADHD. Believe it or not, statistics show up to 80% of adults with ADHD are not even diagnosed or treated, although I think we're making some progress there. As we know, untreated ADHD leads to multiple bad outcomes, the worst of which I mentioned, premature death. Now, adult ADHD is also highly comorbid. It is actually very unusual to see someone, whether adult or child, who has just ADHD. I mentioned medical comorbidities. There's also significant psychiatric comorbidities. Way more likely to have depression, even bipolar disorder, substance abuse. ADHD is, among other things, dysregulation of dopamine. Dopamine is pleasure, it's motivation, reward. All drugs of abuse raise dopamine. They're sort of trying to self-medicate. In adults, the vast majority, they said depression and anxiety are the top two by far. Substance abuse, maybe bipolar and so on. Often ADHD is missed because in adults the presentation is often the comorbidity. They present with depression or anxiety and people will treat them with often SSRI type medicines, SNRIs, they don't work for ADHD. This contributes to people being treatment resistant, if you will. Now, the landscape of medicines that are FDA approved and or evidence based is here. We basically divide the categories into stimulants versus non-stimulants. The stimulants, there's two flavors I can prescribe: methylphenidate and amphetamine. Both of those have as part of their mechanism reuptake inhibition of dopamine and norepinephrine. They block those transporters. Solriamfetol does have that in common, potentially, partly, but they do other things as well. Of course, those are highly abusable, controlled substances. One of the nice things about solriamfetol is it's already on the market, it's already gone through the scheduling process. It's considered a non-stimulant and it's Schedule 4, not Schedule 2. Schedule 4 for me as a prescriber is what I call a speed bump. Schedule 2 is a roadblock. Not as big a deal. We have two drugs approved for adults that are called norepinephrine modulators. Atomoxetine is the old stroke. Viloxazine extended release is called Kelbri. Big news, there's a label update, viloxazine now also got in their label that it modulates a serotonin receptor and it actually binds to three different serotonin receptors, which is interesting. It was historically an antidepressant in Europe for many years. Atomoxetine, I did one of the original studies with atomoxetine for depression and it failed. It was originally being developed as an antidepressant. Norepinephrine reuptake alone is not an antidepressant. You need to do other things. The alpha-2 agonists, we have extended release clonidine and guanfacine. They're FDA approved in kids, but not in adults, although they are used in adults and off label. I want to highlight bupropion here. Bupropion is used quite a bit. There are case reports and I was actually, no, I won't tell that story. I, amongst others, were urging GlaxoSmithKline to study it. It could have been the first non-stimulant for ADHD. There's a reason they decided not to. Not everybody's as creative as this company, I would say anyway, but it's used quite a bit, especially ADHD with depression. We have others. Modafinil is a wakefulness promoting agent and there's some others. Solriamfetol has already gotten some play. There was a pilot study done by my friend Craig Surman up at Harvard in adults with ADHD that was positive with Sunosi, and that sort of was the basis to go forward. Limitations. Stimulants, as I mentioned, are abusable Schedule 2. It's become increasingly more difficult to prescribe Schedule 2 drugs because of the opioid crisis. Lots more hurdles and difficulties for prescribers. There are potentially cardiovascular effects. Insomnia, we know irritability, rebound when it wears off, decreased appetite and weight, although that's less of a problem in adults. Non-stimulants just don't work as well, number one. I like to say nobody really wants to prescribe a stimulant, but I have to because they work so darn well, in a sense. What I need is a non-stimulant that really works. Slower onset of action, not working as well, and there's some other issues. If you look at the landscape on the right, what we have is the breakdown of what medicines are used in adults. The majority of treatment is with amphetamines. There's some methylphenidate and some non-stimulants. In kids, more non-stimulants, but way more methylphenidate. There are historic and other reasons why there's that distinction between methylphenidate in kids and amphetamine in adults. The point is, the vast majority is still stimulants. I want to talk quickly about the FOCUS study, which you can see here is a Phase 3 study with Sunosi for ADHD. Any way I look at this, this is a positive study. I love Dr. Cummings set me up beautifully for this, guys. Studies fail in psychiatry. Some people have estimated 50% of our studies fail. They don't fail because drugs don't work. They fail because placebo works too well. Now, does anybody here think Prozac is not an antidepressant? Before Prozac was FDA approved, there were 11 studies done. Six of them failed because placebo worked so darn well. It's not unusual, as Dr. Cummings said, to have a study that fails. Here we have a positive study, and I'm really excited about it. We also have, so going down on this graph is good, by the way. That's decreasing ADHD symptoms using a standard adult ADHD rating scale. One of the things that stands out to me is I'm starting to see efficacy at week one. With ADHD, with the non-stimulants, it can take a couple of weeks. Usually when somebody comes in to see me, it's pretty urgent. We got to try to get them better. You can see out to six weeks. The way I read this, while the 150 was statistically significant, the 300 is absolutely working. You can see those curves are superimposed. There was just a little teeny blip at the end, just a random blip of the 300. Because placebo response was high, you lose statistical significance. If I just look at those two curves, that's a drug that works. That's really exciting. Also, it's a very big drop in the rating scale. We're talking about a drop that's approaching 18 points. That is as high as anything I've seen and I've done dozens of ADHD studies. Side effect profile, no new safety findings, well tolerated. I'll tell you, I was very, I got a parenthetic. I was incredibly surprised how well tolerated it was for agitation and dementia patients. That was quite impressive. Moving along now. This is, and Dr. Cummings set me up beautifully for this too. I'm also a big fan of this rating scale, the CGI-S. The CGI-S, Clinical Global Impression Severity, is you as an experienced clinician taking everything into account. How sick is this patient at this moment? They come in moderate or moderately severe. What I love about this is it takes into account not only symptoms, but function. Most of our rating scales that are primary outcomes are symptom based and that's fine. In the real world what matters is quality of life and function. This captures the whole gestalt. What we see here is again evidence that it is working as early as the first week and it's significant all the way along. I like that this is now saying not only is their symptoms improving, but perhaps function and could include relationships. It's basically taking everything into account, what the spouse tells you, everything. I alluded to this earlier. This is a comparison of the drops in the ADHD rating scale scores with various medications. What you see here is solriamfetol is on the left towards where stimulants live, again about an 18 point drop. If we look at some non-stimulant comparators, atomoxetine and viloxazine are down there in the 14, 15 point range. This is not head to head data. It's very risky to make comparative claims like this, but it's helpful to put in context perhaps the magnitude of improvement. If we could just now summarize, ADHD is a chronic, serious, lifelong condition that really impairs people's lives, associated with significant medical and psychiatric comorbidity, associated with shortening of your life for various reasons and treatment. By the way, I forgot to mention there are now a couple of studies that show that treatment actually decreases the premature mortality risk. Initially you're going to decrease suicide and accident, and over time you see a decrease in the cardiovascular and diabetes and other related deaths. You heard also they smoke more as well, so perhaps you can also make a dent in smoking and substance abuse. Unfortunately, not all of our drugs work. Some have tolerability issues, stimulants are controlled substances, and have all of that baggage. Sunosi is a novel agent. It's a DNRI, highly potent with TAR1 agonism, which modulates monoamines and glutamate. Sunosi showed significant improvement, as you saw in the ADHD symptoms in a Phase 3 trial. Well tolerated, safety profile similar to what has been seen before. I believe I'm going to move on to the end and then we'll take questions at the end. Is that true? Yeah. Okay, we'll keep moving and let me see how I'm doing here. Okay. All right, let's shift gears and talk about MDD. I certainly don't have to tell you how common MDD is. As a matter of fact, it's the number one cause of disability in the world, according to the World Health Organization. Think about that. It's more cause of disability than cancer, heart disease, anything else you can think of. It's quite amazing. We know that our standard antidepressants, such as SSRIs and SNRIs, are inadequate. Only a third of patients get to remission. Maybe half respond to some degree, and that's inadequate. It is common, as we see here. I remember when we used to say it was only 16 million per year. It's now up to 21 million. Especially since COVID, we've seen the incidence has been increasing quite significantly. Serious condition that also affects people's lives, as you know, and is also interestingly associated with significant medical comorbidity. There is a clear association of obesity, cardiovascular disease, and diabetes, again with people with depression. Now, the two sort of deal breakers of our antidepressants are weight gain and sexual dysfunction. The SSRIs and SNRIs can do that, and also a sense of fatigue and feeling blunt. We need more new mechanisms, obviously. Now, if we focus in on the subpopulation with excessive daytime sleepiness, or if you want to call it fatigue, that's fine. This is a significant subgroup. As many as 50% of patients have this condition in addition to their depression. If we look at large studies like this one here, over 1,000 adults, the history of depression was associated with a significantly increased risk of excessive daytime sleepiness. Depression was the single strongest predictor of excessive daytime sleepiness. Even when you take into account sleep apnea and obesity, and severity of depression is linked. If you have excessive daytime sleepiness, that means you're going to have a worse depression, you're not going to respond as well to treatment, you're more likely to relapse, you're just not going to do as well. Certainly we have drugs approved to treat depression, but none to treat depression with sleep, excessive daytime sleepiness, or fatigue. Now why is this so important? Just because it's common? Because our current treatments don't do such a great job treating it. This is a study that was done by Maurizio Fava and his friends at Mass General. Basically, what you see highlighted here, using two different self-report rating scales, is that excessive sleepiness and fatigue are some of the highest residual symptoms. These are treatments with reuptake inhibitors, SSRIs, and SNRIs. They just don't treat this very well. Especially if you look at the graph on the right and you put the first three groups together, to me, this is kind of a cluster that goes together: decreased motivation, trouble with sleepiness or wakefulness, and energy. Those are all kind of related because if you're tired, you're not motivated. This is a huge problem. These are people, again, who are considered successfully treated but still have these residual symptoms. If we look at the next slide, what you see is not only is it not well treated and often residual, it can actually be brought on by these drugs. When you just raise serotonin, you downregulate dopamine, and dopamine is wakefulness, it's pleasure, it's cognition. You can see here that you even have some treatment-emergent sleepiness and fatigue and feeling blunted. Our current treatments are not good at this particular cluster of symptoms. As I mentioned, this particular symptom or cluster of symptoms is related to poor outcomes. Patients with hypersomnolence had greater depression severity, higher rates of suicide. Did you know this is associated with suicide? It's also associated with anhedonia, parenthetically. Anhedonia is the single highest cause of functional impairment and it's linked to suicide as well. Also, hypersomnolence is an independent risk factor showing that you're not going to respond. If you look on the right, you have more suicidality, more severity, and less good response. We really have a significant need here for things that work for this subpopulation of patients, which is a big subpopulation. Here we have evidence from a clinical trial. This is the PARADIGM study with Sunosi for depression. In a subgroup who had excessive daytime sleepiness, what you see here, again, going down is good. That's improvement in depression using a standard depression rating scale, the MADRS, Montgomery-Åsberg Depression Rating Scale. You can see here, at the end of six weeks, those who got Sunosi had more improvement in their depression. This is measuring depression, not sleepiness, guys. You can see we've beat placebo. I can imagine a question could be, you're just, we know this drug works for sleepiness, you're just treating sleepiness, and depression looks better. It turns out if you sub analyze these data and look, taking out fatigue and sleepiness and just look at depression items, it still works. This drug is an antidepressant. Of course, it's not a surprise if you look at that mechanism. That's Wellbutrin on steroids, if you will, with TAR1, which in preclinical animal models is an antidepressant, modulates the things we want to modulate. There is every reason to believe that this drug is not just treating the sleepiness. We know it does. It's wakefulness promoting, in a sense, but also that it is treating core symptoms of depression. I'm very excited about this. This is looking at overall depression severity, again using the CGI. This is the CGI. Excuse me. This is the patient's rating. The CGI is rated by a clinician. Of course, when I do a CGI, I talk to the patient, I talk to their family. This is just asking the patient. PGI-I is the patient's global impression of improvement, not severity. We're setting the bar very high here. We're asking them to say the highest level of improvement because this scale has a couple levels of improvement. The highest level is I am very much improved, taking everything into account, and you can see here, more than twice as many patients rated themselves as very much improved. They were noticing something as well, and that's important. The FDA increasingly is looking at patient reported outcomes. We call them PROs, patient reported outcomes. If I could summarize, about 50% of patients with MDD, which means many million. If it's 21 million, we're talking over 10 million people in the U.S. It's associated with poorer outcomes, however you slice it, including suicide. Sadly, early clinical evidence supports continued development of solriamfetol for MDD, especially with excessive daytime sleepiness, and it could be the first treatment with such an approval. Why else is this important? I was telling Herriot earlier today, I do promotional speaking, I do talks, including I'm a speaker for Axsome, I should disclose for Auvelity. When a new medicine comes to market like this, clinicians always ask me, who's the Auvelity patient, let's say. Often I can just say, they have to have depression and I don't have a lot of other data, although Auvelity has some really convincing data for that anhedonia symptom I mentioned earlier and Roger McIntyre and I just published expert consensus guidelines on anhedonia and we reviewed the world's literature. There's only a handful of drugs that have ever shown evidence of efficacy on anhedonia and Auvelity is one of them. I can say that. To be able to say this, here's the patient, this paints a picture in a clinician's mind right away, they know who this is. I think that's extremely helpful because if you're approved for everybody, you're not going to get used. You're approved for nobody, essentially, I would think. This really helps, I would say, and it also helps me to know what patients am I going to really fight for this. Finally, we're going to talk briefly about shift work disorder, which you may not realize how common this is, but there's about 15. Actually, let me start to the right of the top line and go left. I think it reads better. On the right, about 1 in 3 people working in the U.S. work an alternate shift. I'm pausing for dramatic effect. That surprised me when I saw that 10% to 43% end up with shift work disorder, which means perhaps as many as 15 million people in the U.S. This may be a little surprising to you. It certainly was to me. How do we define this? If you look on the left, shift work disorder is a combination of excessive sleepiness during the time you should be awake and persistent insomnia during a time you should be sleeping. Your circadian rhythm is out of whack. It's long been associated with multiple serious health problems. We know, for instance, that insomnia and disrupted circadian rhythm is clearly associated with obesity, cardiovascular disease, and diabetes. I know I sound like a broken record here because I'm saying the same things, but it's absolutely true. Also, a much higher risk, as you can see here, of having a work-related injury if you're sleepy. Of course, no new medications approved for this condition since 2007. Unfortunately, residual sleepiness is a problem because usually what people are doing is they're taking something to knock them out to go to sleep when they're supposed to sleep. Here we have something that might treat the opposite end. It might help you with being awake when you're supposed to be awake. It is very important to try to regulate that circadian rhythm. I'm also excited about this indication, to be honest. I think it's, again, very out of the box and creative of Axsome Therapeutics to be thinking of some of these conditions. They are precision based and mechanism based. They're looking at the mechanism of action, saying, you know, what other unmet needs are there? What else could this help with? With that, I believe that's the end of my formal. My friend Dr. Susan McElroy is coming up with that. I'm going to stop and address any questions that you might have. Thanks, Dr. Cutler. We have about 10 minutes for questions. Mics are going around the room. Hi. Hi. Amy Fatiha from Needham. Thanks for taking my question. Just with regards to ADHD, can you. Talk about where you see Sunosi fitting. In the market, given that there are. A lot of generic treatments that are available and used. Can it differentiate itself on efficacy versus the stimulants? Where do you sort of see it being used if it comes to market? Sure. When you're talking about generics, the only generic non-stimulant that's approved for adults is Strattera or atomoxetine. That's been a very disappointing medication. I'll be very honest with you. It works maybe 30% of the time. I think there's a huge place for this medication. If I had a non-stimulant like this, I would certainly want to use it first of the non-stimulants and possibly even before. Why even use a stimulant if I don't have to? I think what happens is a lot of clinicians, they don't look at this data as carefully as you guys do. I hate to break it to you. They're not teasing it apart like you guys do. I think it's great that you do that. Keep us honest, do that. They just don't. They sort of feel like these trials aren't necessarily my population. They know that if the study is positive and the drug is approved, they're going to try it. Right. They're going to vote with their feet. I can tell you this drug works and I think it's going to get used and myself. There's some other ADHD KOLs that have been talking about this and we're very excited. We think that this is actually going to be probably the winner of the non-stimulants, especially the couple that are coming out. We're excited about it. I don't want to sound too Pollyannaish because there will be issues, of course, but I think the fact it's already on the market, it's already gone through the scheduling process. There's a lot of confidence and a lot of familiarity. I think those will all help. Also, as I mentioned, one of the top comorbidities is depression. I think the mechanism predicts you're going to get a 2-for-1 deal instead of a stimulant plus an SSRI or SNRI, which we have a lot of patients like that. This may be two birds with one stone. Clinically I think it's a big deal. Hi, Andrew, it's Hyer from Jefferies. Can you speak to the importance of needing to titrate or having a flexible dosing schedule in ADHD for both children? And. If you're the company, would you be running multiple doses in their next study? Okay. Where's Sue? I've been beating the company over the head about that, actually. I shouldn't say that. Beating over the head, absolutely. There's no one size fits all dosing. We know that it's very helpful to have multiple doses, and the company is looking at multiple doses. Titration is helpful because not everybody responds. We know there's a lot of genetic variability in metabolism, metabolism in response to medications. It is very helpful to have more than one dose. I think what's encouraging is we did see evidence of efficacy here as early as the first week, but people will want to dose optimize, dose individualize. I think that's going to be another positive. We have several dose strengths already available for EDS. The potential to have the 300 mg dose approved would be nice. There is clearly evidence from the excessive daytime sleepiness trials of a dose response. Even when you do fixed dose trials, if you look at 150 versus 300, even if you don't see a clear difference, that's averages, individual patients. I promise some will need a higher or lower dose. Hope that answers your question. It's a great question. Thank you. David Amsalem at Piper Sandler. Just along the lines of Sunosi and ADHD, let's assume that the label is expanded to include ADHD and let's also assume that it's approved in both children and adults. Yeah. How do you think about usage of the product in practice in both the. Pediatric population and adults? You made a comment earlier that you lean more into stimulants, more into amphetamine and methylphenidate. I don't personally. The market does that. The market does. There's a reason that happened, and I can explain it later. Yeah. I guess my question here is where would solriamfetol fit specifically in kids? Where would it fit into adults? Since adults seem to comprise the larger chunk of the market, how would you think about using solriamfetol in your, quote, stimulant-experienced patients? Sure, sure. All great questions. First of all, we do tend to use more non-stimulants in kids for what I would call obvious reasons. Any of us who are parents know I would rather not put my kid on a stimulant, you know, if I have to. I have here potentially an effective non-stimulant that doesn't have theoretically as much of the cardiovascular risk or the decreased appetite and weight loss growth problems. It's not sedating like the alpha-2 agonists. They're very sedating. I think it has a lot of reason to think it's going to get used quite a bit in that population. In the adult population, like I said, there's sort of already this use of bupropion and bupropion's data is not strong, some case reports, but here we have a medication that to me looks like it's going to be more potent. There's already a kind of natural niche. Also, there's a lot of adults who either I don't want to use a stimulant or I can't use a stimulant. Another population that's just perfect for this is the younger adults in the college age years. That's when stimulants get diverted, abused. If a kid goes away to college, it's very hard for me to prescribe stimulants across state lines, controlled substances like that. In older folks where I'm very worried about cardiovascular issues and so on. In patients who have the comorbidity, as I mentioned, of depression, to me this is a no brainer and we're talking about 40% to 50% of ADHD patients have comorbid depression. I don't want to over promise here but I think there's a lot of rationale to think about places where this would get used. As I said, clinicians vote with their feet. They'll try it, I think they'll see it works, they'll like it and they'll keep using it. Hi there. Thank you for the presentation. Jotham from TD Cowen. Maybe first on the ADHD side. On the data that we've seen. Far, do you expect it to work? In the pediatric population? I guess when we look at that trial design, what are some important characteristics? To be on the lookout for there? On the shift work disorder indication, obviously indicating 50 million U.S. workers may suffer from the disease. How many are actually diagnosed and seeking therapy? Just given the innovation in this area has been a little light. Great question. Let me start with this last part because it's a little quicker. If a medicine hasn't been approved since 2007, that means nobody's been talking about it because nobody's promoting. Nobody's talking about it. I think if you now have a medicine approved since, see, what FDA approval gets you is two things. It gets you reimbursement, but it gets you the ability to educate and promote. I think if we start raising awareness and educating, I think that there are a lot of people out there who will kind of come out of the woodwork, if you will, or will start recognizing. You'll hear my friend Dr. Susan McElroy talk about binge eating disorder. I was involved in the binge eating disorder trials with Vyvanse. I can tell you that shocked me. That was a hidden epidemic. I had no idea when I started recruiting how easy it was to find those people. I think something similar might be going on with shift work. I forgot to mention the FDA will not approve a drug just for adult ADHD. They will have to do child studies. You're right. It's a little bit unfortunate, to be honest. The FDA sees it as a childhood disorder, starting in childhood. The drug will get used and it's fine. We should do that. Typically, some of the studies you may have seen are the laboratory classroom design studies, which I've done many of those. I'm an investigator on those. I have recommended to the company against doing that because those are specifically, they were specifically designed to look at extended release stimulants, to look at duration of action. That's not an issue with a non-stimulant. It never has been. Back then there was the competitive wars between the extended release stimulants, who lasts longer, and they would do those. Those are very labor intensive. There's only a handful of sites in the country who can do them. I think just straightforward child studies are fine and that's what I would do. Like the gentleman said earlier, I would probably use a couple different doses, maybe a little bit lower end, maybe 75 and 50, because we want to have a range of doses available. I wouldn't get too fancy or complicated. I think it's going to work, I'll be honest. Should. Hi, David Huang with Deutsche Bank. I just want to ask about it. In terms of duration of therapy. is potential for switching of therapies in ADHD. Sure. Could you just tell us a little? Bit about once a patient gets started. On drug, you know, how long do they typically stay on it? Do you think there's opportunity for Sunosi. To come in here and capture switch. Patients or with to be kind of. More new starts, naive patients, and then does that differ between adults and pediatrics? Thanks. I forgot to mention, part of the question earlier was what about in people who have had stimulants? Surprisingly, I'm an author on the Viloxazine XR adult studies, and we did a sub analysis of people who had been on stimulants, and they did just as well on Viloxazine XR as those who hadn't been. Just having had a stimulant does not necessarily predict you won't respond or appreciate taking this. Sorry, what was the first part of your question? Yeah, just in terms of duration and switching. Duration is not good. We call it persistence. We know that a high percentage of people with ADHD stop their medicine within a couple months on average, certainly by the end of a year. You're lucky if you have 25% still taking medicine. I don't think it's that simple because what happens a lot of times is people come on and off the medicine, and nobody wants to take medicine. What happens is I think people sometimes learn over time when they come off the medicine and they start suffering consequences again. We see a lot of that kind of thing happening. Now, would this be a first-line medicine in an ideal world? 100%. I would want to use this first line all day long. There's a little problem we have these days that insurance companies like to practice medicine without a license. I don't know if you've noticed that, but they sort of dictate. That was meant to be funny. I guess it wasn't very funny. Meant to be a little bit of a little chuckle there. I may have to start with something generic or cheaper, but I can certainly make an argument there's not really a generic equivalent here. Bupropion is not FDA approved for this use, and certainly this mechanism is very different from viloxazine or atomoxetine. I'm not worried about people switching or trying something else and trying this and not having a good experience. Also, part of the problem with persistence is most adults are getting stimulants. It's just a pain in the butt to prescribe, but also to be the patient getting stimulants. You only can get a month supply at a time. I can't call in refills. You have to come into the office a couple times a year. Nowadays, we're obligated to monitor people in person and get their blood pressure, for instance, and so on. There's the stigma of getting a controlled substance, worrying that the pharmacist is going to look at you funny. There are a whole lot of reasons probably why people don't stick with their medicines, and some of them this may address. I'm not going to say we're going to solve that problem, but I think if you have a medicine that is a little more convenient to use and does work, with a little less baggage, perhaps people will at least stay with it or come back to it. That's sort of my hope. Junli from Truist, for shift work disorder, what % of patients are adequately treated for EDS by treating for their insomnia? What % would actually need both? Treatment for EDS and insomnia? The problem is that most of the time they're, as I said, they're taking something for the other end of the spectrum to help sleep, if you will. That's not necessarily addressing the daytime. Now people are using, for instance, modafinil, a wakefulness-promoting agent. I don't know. I'm not an expert in the market, so I don't know that I can tell you there's probably a significant proportion of people who are not treated at all or perhaps inadequately treated. I can tell you that I don't know the details of it. A marketing team might be able to get you some data. Other questions? Thank you. Great. Thank you again, Dr. Cutler, for sharing your expertise with us today. I'm pleased to welcome our next. Speaker who will be joining us virtually. Dr. Susan McElroy will be discussing binge eating disorder, the fourth indication that we are currently evaluating for Sunosi. Welcome, Dr. McElroy. We'll turn it over to you. Thank you so much. Can everyone hear me okay? Okay. All righty. I think so. Can people hear me? Yes. Yes. Jump up and say yes. Yeah. Okay, thanks. I'm so sorry. We can hear you. Okay. Okay. I got sick. Axsome has been so kind, so I'm doing this from my home, so I apologize, but I'm just really excited to get to talk about binge eating disorder, which my colleagues and I have been working on the past 30 years. Let's just go to the next slide, please. All right. Binge eating disorder is an eating disorder. Most people don't know what it is. Most doctors don't know what it is. Despite that, it's the most common eating disorder in adults and in adolescents. Interestingly, unlike the other two major eating disorders, anorexia and bulimia, which are way more common in women, binge eating disorder is more common in men. There's still a female preponderance, but you see a lot of men with BED. I'm going to give you an incredibly rapid overview of BED. Binge eating disorder is considered a biological, somewhat inherited disorder that involves—we're beginning to figure out the brain abnormalities in binge eating disorder, and we think it involves problems with food reward and appetite regulation, which, if you listen to the news and you hear about the obesity epidemic, you know, it's really important. Binge eating disorder is an incredibly important public health problem that is associated with extremely high rates of both medical and psychiatric disorders. Next slide, please. It took a long time for the field of psychiatry to formally recognize BED, because I think eating disorder people had a very hard time understanding that people could binge but not purge, and then they end up getting obese. I'm going to review for you the DSM-5 criteria for BED, which are just a little over 10 years old. BED was not in the nomenclature until 2013. Here it's the most common eating disorder, but it's not recognized by the nomenclature. BED is easy to diagnose if you know what to ask for. It's basically defined as an individual who has recurrent episodes of binge eating without purging. Binge eating actually has a good definition in DSM. I'm not a fan of DSM for a lot of things, but I think DSM's done a pretty decent job outlining potential diagnostic criteria for binge eating disorder. The core symptoms of the disorder are that people binge. What's a binge? An individual eats an unusually large amount of food for the situation, and that's sometimes complicated to figure out. Plus, almost more importantly, they feel out of control of their eating. I'm convinced people have a really hard time understanding not being able to control your eating, just having done this, treated these patients for so long. People understand loss of control over alcohol. They understand loss of control over gambling. They understand loss of control over sex. People have a very hard time understanding loss of control over eating unless they have it. Just to further inform you about the DSM-5 criteria, there are some other associated criteria that are associated with binge eating, but they're sort of important, though they're really not as important as the two major symptoms, which are eating an unusually large amount of food and feeling a loss of control of eating. There are some other loss of control items, and then the DSM provides additional characteristics, some of which I agree with and some of which I don't. According to DSM, you're supposed to be incredibly distressed by the binge eating. A lot of people are, but not everybody, and I can go into that. If you think the person has bulimia or anorexia, those diagnoses trump binge eating. Next slide, please. Binge eating disorder is an enormous public health problem, despite the fact that it's been recognized just recently. So many people in the medical field and the public just don't understand it. It's the most common eating disorder, not just in adults, but adolescents. It's associated with significant functional impairment. It's associated with incredible distress. It's associated with profound psychiatric and medical comorbidities, in particular, obesity. I think it's really important to remember that there is a very strong link between BED and obesity that we don't fully understand other than it exists. Next slide, please. Most people with BED are unrecognized and not untreated. We've done a number of randomized controlled trials of medications in BED, and people don't come with a diagnosis of BED. You have to advertise the symptoms, and often when you enter somebody into a trial, it's the first time they've ever been diagnosed with BED. So. I think it's important to remember that the medical field and the public still don't have a concept of what BED is. They just don't. We still find so many people who never were diagnosed before. When it comes to how you treat BED, I think it's important to recognize that standard treatment options have not been worked out. There's no consensus on how to treat BED. We got the psychologists who say it should be cognitive behavior therapy and behavioral weight management. We have the psychiatrists who say it should probably be medication based. It's just important to recognize that this is a profoundly common psychiatric disorder that has one treatment approved, one approved treatment, and that's Vyvanse, which is a stimulant that's lisdexamfetamine. The program sponsored by Shire that led to the indication of lisdexamfetamine and BED was, I would say, ridiculously positive. It was just, it was ridiculous. It was a very well thought out program, all sorts of studies, it was positive. That didn't seem to move, despite all of a sudden having this positive treatment, this effective treatment. In my opinion, it didn't really move the needle on people being recognized for BED and people getting treatment for BED. I think it's important to remember that it's BED that is a very common disorder that only has one FDA approved treatment and that's lisdexamfetamine, you know, stimulant, lisdexamfetamine or Vyvanse. There are problems with that. Next slide please. Our group thought up, let's try solriamfetol in BED. These are the rationales for trying solriamfetol in BED. Number one, solriamfetol is a dopamine norepinephrine reuptake blocker, and both dopamine and norepinephrine are involved in the pathophysiology of BED. There is one drug that is a DNRI, dasotraline, that has been studied in two double blind placebo controlled studies of BED funded by Sanofi. The studies were very, the design of the studies was very similar to the design used by the studies of lisdexamfetamine. Both studies were incredibly positive. Dasotraline, a DNRI like solriamfetol, reduced binge eating, it reduced all these other aspects of eating psychopathology, it reduced weight. Apparently, I think it was associated with too many side effects, so it did not get further developed. Okay, so that's actually a pretty strong rationale in and of itself for trying to solve reboxetine and BED because it's a DNRI just like dasotraline and we know dasotraline works in BED. We have a growing body of data showing that medications that act centrally, act on the brain and reduce appetite and weight, that have been studied in binge eating disorder, have been positive. It doesn't really matter the mechanism of the weight loss. If a drug that acts on the brain causes reduced appetite and weight loss, there's a very good chance it's going to work in binge eating disorder. Sunosi has effects on appetite, food consumption, and weight. It reduces appetite, it reduces food consumption, and it reduces weight. Just based on that, it remains an incredibly good candidate for efficacy in BED. Finally, this is just something because our group does a lot of research in BED. There's a very interesting link between narcolepsy and BED. This is something that's been identified, but it's not well understood. It's just that people with narcolepsy have high rates of binge eating and we need to learn more about that. It's led our group to want to study drugs effective in narcolepsy in people with BED. Next slide, please. Axsome Therapeutics is sponsoring an ongoing Phase 3 double-blind, placebo-controlled trial of Sunosi in patients with BED. It's dose finding. The design of the study is very similar to the design used for both the lisdexamfetamine studies as well as the dasotraline studies. These are people who have to have moderate to severe BED and they get randomized without any psychiatric comorbidity, which you can find these people. They get randomized to either a high dose of Sunosi, 300 milligrams, a midway dose, 150 milligrams, or a placebo. We're over halfway through, we're plowing through. All I can say is that having done lots of BED studies—topiramate, Vyvanse, dasotraline—patients tolerate this drug well. That's all I'll say. Next slide, please. What are the key takeaways? First of all, thank you. I'm so happy whenever anyone will listen to me talk about binge eating disorder because it's such a common disorder. I've been working on it for 30 years and it's so neglected. Key takeaways: this is a very common disorder. I think it's much more common than our research exists. It is linked with psychiatric comorbidity and with medical comorbidity, particularly obesity. We only have one medication approved for its treatment. That medication works, but there's problems with it. You know, as Dr. Cutler talked about, it's a stimulant. It's just a pain, it's pain in the rump to prescribe a stimulant. Our group, we're actively studying Sunosi and we think this potentially will be an incredible treatment for these people who are suffering. Okay, is that it? Thank you, Dr. McElroy. We have about 10 minutes to take questions from the audience. Hey, Matt Hershnorn from Oppenheimer, thank you so much for your perspective and taking the question. Something we were wondering is just how often patients are prescribed GLP-1s to help control BED, presumably when they're already obese or overweight. Just thinking about potentially patients who are already on GLP-1 therapy, how could they potentially additionally benefit from, sorry, Lampitol? Also, could you imagine patients potentially discontinuing GLP-1 once they've already addressed the behavioral components leading to their obesity through BED, especially considering the tolerability and cost challenges of BED while they could stand soriel chronically. Okay, those are fabulous questions. I wish I had answers. Like I said, drugs that work through the central nervous system and reduce weight that have been studied in randomized control trials work in BED. Our group has tried very hard to get some company-sponsored studies of GLP-1s in BED and we have not been successful. We do not understand that. We think that people with BED, who are often obese, are getting treated with GLP-1s without necessarily telling their doctors they have BED. So. It's been a huge because, okay, I'm one of the few psychiatrists who prescribe GLP1s to psychiatric patients, but we need to. Do I think GLP1s work in binge eating? I think they probably do, but we don't know, because there's never been studies, despite all these studies in obesity. What our group has seen, as we've seen, people who are obese with a past history of anorexia have their anorexia triggered by these compounds. It's the dilemma of eating disorders are ridiculously common, but they're ignored and they're being ignored right now by the companies that manufacture GLP1s. I know I'm not answering your question, so if you've got a follow up, please ask. Oh no, that's helpful. Understood and makes sense. One follow up, I guess was just in comparison to Sunosi. Just what supports your confidence in solriamfetol from a pharmacological perspective, and how does that inform your expectations for Axsome's Phase 3 trial? It's better tolerated and I don't, I can't, I don't have data. Our group was involved. It was my idea to start to look at desotraline in BED because drugs that work in ADHD that are associated with weight loss, that was one of the major rationales that led us to look at Vyvanse in BED. Our group was involved with both. I think there are phase 3 trials in BED and they were very positive, but the drug was very activating, it was not well tolerated. What's interesting is that this compound, even though it supposedly has the same mechanism of action and patients like it, it's well tolerated. I'm sorry, that's not terribly scientific. That's just based on the observation of our team and we've been doing binge eating studies for like 20, 30 years. Got it, that's helpful. Thank you. Hi there, Joe Thom from TD Cowen. Can you talk a little bit about? The consistency in behaviors across the BED patient population? I guess as it relates to what you would expect from variability in the placebo arm of the Phase 3 study. Perhaps relatedly to the company, what are you doing to help mitigate? Placebo response in this patient population? Right. If I understand. I think you're asking an incredibly important question and pardon me if you're not. One of the problems with BED is that it has a very high placebo response, just like other psychiatric disorders, you know, depression, mania, Parkinson's, pain. Whereas obesity does not have that high a placebo response. It really doesn't. The way the DSM defines BED is you have to have binge eating episodes and you have to have a certain number. We've designed our studies based on that. We've done studies where in order to get randomized, you have to have at least moderate to severe BED. In other words, you have to have at least three binge eating episodes a week. Most studies don't do that. It's what the pivotal topiramate study did. It's what all the Vyvanse studies did. It's what we did with desotraline and it's what we're doing now with Axsome. We're doing this because we know that BED is associated with a high placebo response. We know one of the factors associated with high placebo response is reduced severity of binge eating. We want, in order to try to maximize a signal between drug and placebo, people binge eating at a certain level. They're not hard to find, but yes, there are tons of people who are binge eating at lower levels. What we have ever since then, for the topiramate study, the Vyvanse, desotraline, we've always said you have to have at least three days where you have binge eating per week for two weeks in order to be randomized. That's how we're trying to deal with the placebo response. Since doing that, topiramate has worked. Vyvanse worked incredibly well. Desotraline worked, and a drug that affects orexin did not work. All right, thank you, Dr. McElroy. That thoughtful overview and your perspective on. The substantial needs in binge eating disorder. Thank you for joining us today. We'll now take a quick 10-minute. Break. We'll see you back here in a few. Thank you. Mirror this town. Now I got to. Cut loose please, Lou. Pull me off. Off my knees, Jack, get back. To tell you. Come on, come on. Let's roll. Everybody come through, come on. In many ways. I want you. To stay sometimes when we want. Young, how many have fun always, always. The promise is they break me sometimes, sometimes all my. I will do my best. My side, your head's not right. I still always d together we fall. Apart, yeah, I think I'll be all right. I'm working, so I won't have to try so hard. Tables and turn sometimes. Now my fears, they come to me in dreams, so I sometimes. Are lacking today. I will try. At my best, you say you want. To stay by my side, darling, your head's not right. I see how we stand together. We F. Yeah, I think I'll be all right. I'm working, so I have to try. It was a chance sometimes. I. Got my first real six-string, bought it at the five and dime. Played it till my fingers bled, was the summer of '69. Me and some guys from school had a band and we tried real hard. Jimmy quit, Jody got married. I should have known we never. Get far, went over back now. Sun seems to last forever and if. I had a choice, yeah, shadows. I be there. Those were the best days of my life, complaining when you. Got a job to do. Back to. You standing on your mama's porch, you told me that you wait forever. Oh, when you held my hand, I knew that it was now. Those were the. Best days of my life, oh yeah. Back in the summer, I next. Forever. Forever. The times are changing. Look at everything that's coming down sometimes when I play that old six string. Think about you wonder what went wrong, standing on your mama's, you told me that it lasts forever. Oh, you held my hand, I knew that it was now. Those were the best days of my life. Oh yeah, back in the summer of 1969, it says you turn around your back on each other. Too good, I can make a promise to your mother. Turn around, back on each other, you say that I've changed maybe. I did, even if I change. What's wrong with it? I'll never let you go. I'll never let you go. I'll never let you go. I'll never let you turn around. I break a promise to your turn. Around back on each other. All friends are gone, gone all the time is. All I know is it's wrong and all I know is it's wrong, it's wrong. There's a reason it's lost on me. Maybe we'll be friends. I guess we'll see. I'll never. I'll never let you go. You go. I'll never let you go. I'll never let you go. Have you? Break a promise to your mother. Turn. Let's turn on each other. Did break a promise to your mother, turn around each other, turning around each. I remember the stupid things, the mood rings, the bracelets, and the beads. Nickels and dimes, yours and mine. Did you cash in all your dreams? I still feel you posting like sonar from the days and the waves. That girl's like a sunburn. I would like to say girl is like a sun. It. What time was gone, and it took me like ages just to understand. I was afraid to be a simple guy. I tried my best to smile, but deep inside my heart I felt it was sh. Like a crowd dancing, I guess I couldn't live without things that made my. Life, what it is, keeps you. You hear it calling everybody. I get out my bed without thinking I was wrong when not feeling cold. This world becomes. Another knockdown one home in your. Arms again, I got a very good friend who says he can't believe the love I give is not enough to end your fears. I guess I can. Live without things that made my life. Can't hardly hear it. Calling. Everybody shaking. Tonight everything is over. Oh, rain falls and hard times coming, they. Won't leave in the night. I wish. I knew I was doing just to. Let the spirit survive. I guess I could live without things made my life. What it is, keep you, we hear it calling. Everybody shaking. In our own little Hollywood, we watch stop stars, but things can be. We got everything we need in our neighborhood, no fancy car. When we were 50, smoking in the bar, we never really noticed you. I was far apart. Remember Jimmy. We’re driving in the dark and think about it now, we didn’t think at all. In our own little Hollywood, we washed up stars. Everything’s got me good. We got everything we need in our neighborhood, no fancy cars. Everything’s got me good. I don’t want to know where it’s going to go, crazy living this life. We’re living in our own little Hollywood, we’re watching our stars. Everything’s got me good and me again busted. Three on the wall left at. Me, rebelliously, with hands tied up and. All I wonder what you've been up to. Jimmy's still the same. The old tree in our backyard, discarded by our neighbors. Hanging on to everyone and all. The time. I don't want to know where it's going to go, it's crazy. We. Got everything we need in our neighborhood, the hood, no fancy cars. Everything's got me good. I don't want to know where it's going to go crazy. Living this life, we're living in our own little Hollywood. We're washed up stars. Everything's going to be good. We're washed. Stop. Everything's going to be good. Hi, everyone. We're ready to begin the next presentation. It is my pleasure to introduce Dr. Michael Thorpy, who will be providing an overview of. AXS-12 in narcolepsy. Dr. Thorpy, please go ahead. Good. Thank you very much. I'm delighted to be able to talk to you about narcolepsy and AXS-12. I'm a neurologist by training. I am also a sleep specialist. Been seeing patients with narcolepsy for over 40 years, based here in New York City at Montefiore Medical Center and Albert Einstein College of Medicine. I'm going to talk about AXS-12, reboxetine. First of all, just a little bit about narcolepsy. This is a novel treatment for the treatment of narcolepsy, and it's a norepinephrine reuptake inhibitor and dopamine modulator. Now, narcolepsy, as you know, has really three main features to it. One is excessive daytime sleepiness, which is present every day and never goes away. It's a lifelong condition. There are abnormal REM sleep phenomena, of which cataplexy is the most prominent one and is the one that's most disabling of the abnormal REM sleep phenomena. There is also disturbed nocturnal sleep. Our current feeling is that narcolepsy is caused by an autoimmune response, causing destruction of orexin neurons. Orexin neurons are very important in stimulating all the wake-promoting areas of the brain. It stimulates all those monoamines that are important in the control, not only of alertness and wakefulness, but also in control of REM sleep. Norepinephrine, dopamine, serotonin, all the monoamines are affected when you lose orexin. The loss then of orexin causes a reduction in norepinephrine and it causes a reduction in dopamine signaling, which is important for the central nervous system. Norepinephrine, we've known for a long time, is involved in narcolepsy. In fact, it goes way back to the 1970s when Dr. Mignot at Stanford did studies with the narcoleptic dogs. He showed that the stronger the norepinephrine reuptake inhibition, the greater the effect on the dog model of narcolepsy and cataplexy. Norepinephrine's always been known. We feel that the loss of orexin affects the stimulation to a lot of these wake-promoting areas. There is also actually some recent evidence just reported at the recent sleep meeting in Seattle a few weeks ago, that not only orexin neurons may be involved in narcolepsy, but there may be actually involvement of the norepinephrine cells. It was reported that there's a reduction in norepinephrine signaling in the locus coeruleus, so orexin and norepinephrine, obviously very important parts of narcolepsy. AXS-12 inhibits the reuptake of both of these neurotransmitters, the norepinephrine and the dopamine, and improves dopamine signaling in the brain, alertness, and improves cataplexy by means of norepinephrine. Narcolepsy. This states that there's an estimation of about 185,000 patients with narcolepsy. We really don't know what the true prevalence of narcolepsy is. Like many of the other presenters who have presented today, they talked about the fact that disorders are under recognized, under diagnosed, and undertreated. That certainly goes for narcolepsy, too. We know from studies that we've done that it can take patients between 8 and 12 years to get a diagnosis of narcolepsy. Many people have narcolepsy and are not aware of it. The main symptoms, as mentioned, are the abnormal REM sleep phenomena and the sleepiness. The primary symptoms that people talk about in terms of the abnormal REM phenomena are cataplexy, which, as I said, is the most disabling. It's emotionally induced muscle weakness. It causes patients, when they get emotional, to get a weakness that can lead them to fall to the ground. Even when they don't fall to the ground, it can be very disabling because it can affect their interaction with people. They can drop things. They tend to be more clumsy. They get slurring of their voice. There are a lot of other features of cataplexy besides the weakness in the legs that cause them to fall to the ground. They get a lot of abnormal REM sleep phenomena, such as hallucinations and sleep paralysis that occur at night or during naps during the daytime, too. Those features can be very disabling as well, as well as a disturbed nocturnal sleep. We don't know exactly how many people have narcolepsy with cataplexy. It's estimated that up to 70% of all narcolepsy patients have cataplexy. It's very difficult to diagnose when someone falls to the ground. It's very easy, but if somebody has just subtle weakness that comes on with emotion, with a little head drooping, some eyelid drooping, or some slurring of the voice, it may be very difficult to make the diagnosis. With regards to the current treatment landscape, there's a survey, the Crescenda survey, that was done on over 200 patients with type 1 narcolepsy. That's narcolepsy with cataplexy. Those are the most severe patients with narcolepsy. Current treatments, as shown in this 203 patients, are that the majority of them were on wake-promoting agents. This is drugs like you've just been hearing about: solriamfetol, modafinil, armodafinil, pitolisant, and oxybates, and then the traditional stimulants methylphenidate and amphetamines. Those are the most common drugs. Very often, most patients with narcolepsy are treated with more than one medication. The combinations that were most common and came out in this survey were the wake-promoting agents plus oxybate, or oxybate and a stimulant, or wake-promoting agents and a stimulant. 30% of this particular population indicated that they were taking more than two medications for their narcolepsy. That's not uncommon. We know that many patients take three or more medications, and in this, 31% were actually taking three different classes of medications. What we use often is drugs of different classes, which helps in their management. You can see that because there are so many medications used in the treatment of narcolepsy, it's a difficult condition to treat. Patients have a lot of adverse effects and change medications very frequently because they're either not getting good efficacy or they're getting side effects, or physicians feel that they're better on a different drug than the one that they're on. 93% of patients report discontinuing some medication for their narcolepsy at some stage. When you look at this survey from the point of view of how patients are doing on their medications, the majority of patients are actually not doing too great. As you can see from this data, 77% of the patients on current therapy for narcolepsy still have some cataplexy, and that can be disabling. Even subtle cataplexy can be very upsetting to a patient. They get to speak to someone and they get a little tense or anxious, and that emotion causes their voice to go slurred and they can't say what they want to say, for example, things like that, or they drop things because they get a little weakness in their limbs. 77% still have some cataplexy, 64% still have daytime sleepiness, and 74% have cognitive impairment. Now, cognitive impairment I didn't mention, but we're becoming more interested in the cognitive effects of narcolepsy. We used to think that it was all just part and parcel of the excessive daytime sleepiness. We now think that the cognitive effects actually might be something a little bit different and may be related to the primary pathophysiology in narcolepsy. Even when patients get improvement in their daytime sleepiness, they very often still have some cognitive impairment that exists. 74% indicating some cognitive impairment, difficulty in multitasking, concentration, memory difficulties, things like that. As you can see, a large number also have disrupted nocturnal sleep. Cataplexy, as I've indicated, really has a profound effect on patients' lives. It can affect virtually everything they do during the daytime. 50% indicated that it affects their day-to-day life, it affects their social life, they can fall down, as I mentioned, it affects professional life, education, and then there's slurring of speech. Narcolepsy is a disorder that occurs. The median age of onset of narcolepsy is 16 years. It's occurring. Half the patients are getting narcolepsy before the age of 16. It's during their educational time. Of course, this is where their education is affected and it often doesn't get diagnosed until they become adults, as I mentioned, because of a delay in diagnosis. Now with AXS-12, there are three studies that were done. The first study, a Phase 2 study, small number of patients, 21 patients, but a two-week randomized double-blind placebo-controlled study looking at the cataplectic episodes. These were assessed on a weekly basis as to how frequent they were getting the cataplexy. This was followed by a Phase 3 study which is five weeks randomized placebo-controlled, again looking at cataplexy episodes. Following the SYMPHONY study, this Phase 3 study, there was an open-label study that persisted for approximately six months. It was followed by a randomized withdrawal portion at the end of that open-label portion of the study, again looking primarily at the primary endpoint of cataplexy episodes. These are the Phase 3 results with regards to the SYMPHONY study, that first Phase 3 study that looked at weekly cataplectic episodes. You can see here the dark line, AXS-12 versus placebo. Clear separation from placebo. Of importance to note is that there was a significant improvement in cataplexy at week one. That's important because a lot of the medications that we use for narcolepsy, you actually don't get improvement in cataplexy for some time after you start, it can be weeks, in some cases even months. Getting a significant improvement in cataplexy at week one is an important finding. You can see that the improvement in cataplexy was statistically significant throughout the remainder of the study up to the five week point. A robust and effective treatment of reducing weekly cataplectic attacks compared with placebo. This is looking at the number of patients that got complete resolution of their cataplexy. As I mentioned earlier, 77% of patients on current treatment reported still having cataplexy. You can see that there were some patients that even at the first week had a complete resolution of whatever cataplexy they had at that time. You can see that there were improvements across the study, so that 33% had complete resolution of cataplexy by the week five of the study. This is looking at daytime sleepiness. This wasn't a primary endpoint, this was a secondary endpoint of the study and it was looking at the clinical global impression scale of severity. You've heard a lot about that today, so I'm not going to explain that. This is where patients were asked about the severity of their sleepiness itself. Again, you can see that there was statistically significant improvement at week one and then improvement across the study, particularly at week five at the end of the study. At the endpoint there was significant improvement in excessive daytime sleepiness as the physicians were reporting their improvement in daytime sleepiness on discussion with the patient. This is looking again at a secondary endpoint, looking at cognitive function that I mentioned to you earlier. This is using elements of the functional outcomes of sleep 10 questionnaire. Again, statistically significant improvement in cognitive function compared with placebo. This is looking at the patients that had more than one symptom sort of resolution. We're looking at combinations of symptoms here. In the first slide you see cataplexy and excessive daytime sleepiness at week five compared with placebo. When you combine those two symptoms together, there's significant improvement compared with placebo, and similarly with cataplexy and cognitive function, if you combine those together, significant improvement at the five-week portion of the study compared with placebo. This is looking at overall Clinical Global Impression scale of severity, looking at the whole condition, and before I showed you the sleepiness component. This is taking everything into consideration as to whether patients overall were improved. You can see again statistically significant improvement at week one, and improvement throughout the study, and statistically significant at the five-week endpoint of the study. I mentioned that the SYMPHONY study was this five-week placebo-controlled double-blind study of AXS-12 versus placebo. At the end of it, the subjects were asked if they wanted to continue into a double-blind portion of the study, into an open-label portion of a study. The patients in light gray that were on placebo were then changed to AXS-12. Through the ENCORE portion of the study, the six-month portion of the open-label, all the subjects were on AXS-12. You can see that the improvement in terms of their cataplectic attacks was maintained throughout the six months of the study with no sign of any rebounding of any cataplexy during this open-label portion of the study. At the end of that six-month portion of the ENCORE study, there was a randomized withdrawal portion so that patients were then in a double-blind manner withdrawn. Half of them were put onto placebo, half of them continued with their AXS-12. You can see that there were statistically significant improvements at week two and week three after being withdrawn from placebo, significant improvements in the group on AXS-12 compared with those on placebo. They had a return of their cataplexy if they went back onto placebo. This looks at ability to concentrate and cognitive function coming from the Narcolepsy Symptom Awareness Questionnaire. During that randomized withdrawal portion of the study, there were significant differences between placebo and the patients who were taking AXS-12. This is in terms of the PGI, the patient assessment of change in their overall condition. As you can see, the patients that were on AXS-12 were improved compared with those on placebo. Patients felt their overall condition was much better when they were on AXS-12. AXS-12 was a safe medication, and there were low discontinuation rates and adverse effects across these three placebo-controlled portions of the study. In each of these studies, all the adverse effects were mild to moderate in severity. They were much the same as the adverse effects that were seen in the earlier studies and tended to be more in terms of milder GI symptoms such as dry mouth, nausea, and constipation. The long-term safety and tolerability was consistent with the short-term studies. No new safety signals were seen in any of these particular studies. The key takeaway points, as indicated here, are that narcolepsy is rare, although it's regarded as rare for people that are presenting because of daytime sleepiness. It is certainly one of the commonest causes of daytime sleepiness. Patients that are presenting to sleep disorder centers with that symptom of sleepiness, up to 70% of them will have cataplexy, which can be very disabling for many of them. Despite current treatments, they can have continued sleepiness, cataplexy, and cognitive impairment. There is clearly a need for improved treatments over what we have at the present time. AXS-12 is a novel norepinephrine reuptake inhibitor, dopamine cortical modulator, and it's important in controlling those sleep-wake neurotransmitters that are involved in control of REM sleep and in control of sleepiness. AXS-12 demonstrated a consistent, robust, efficacious effect and was safe in all of the three studies where it was studied. Thank you very much. We will turn to the audience for any questions for Dr. Michael Thorpy. Hi, Jason Gerberry from B of A. Just curious, what therapeutic modalities you laid the narcolepsy type 1 treatments, right? What loses when orexin receptor 2 agonists come to the market? Of that 38% or so use. Of antidepressants, does it eat into that segment at all? I would imagine that's where the. most logical role for a drug like AXS-12 would be, just kind of curious if you can offer some perspective there. Okay. Antidepressants off label have been used for many years and as I mentioned, they have been studied in the earliest days in dog models showing they're effective against cataplexy. Yes, antidepressants, particularly those with norepinephrine effect, certainly have improvement. There's no FDA approved antidepressant at the present time and the antidepressants have not undergone any rigorous study in narcolepsy, even though they are used sort of anecdotally, so physicians may use them, but again, they really don't know exactly which one to use, how to use it. There are a whole variety of antidepressants that are used in narcolepsy. There's not one that's the main drug that's used when it comes to the orexin agonists. Obviously, there's a lot of interest and excitement over the orexin agonists. The orexin agonists have been shown in early studies to be extremely effective in treating both excessive daytime sleepiness and cataplexy in patients with narcolepsy. At the moment, there's a lot of question with regards to the correct dosing and also the side effect profile with regards to these medications. Some of them, as you're probably aware, have had to be withdrawn. One of Takeda's drugs was withdrawn because of hepatotoxicity. One of Jazz's orexin agonists was withdrawn because of cardiovascular issues. There's a lot of interest in the adverse effect profiles of these medications and the most common side effect is disturbed nocturnal sleep. I mentioned to you that nocturnal sleep is a key feature of narcolepsy. In fact, we regard it as one of the three main features of narcolepsy. Disturbed nocturnal sleep certainly can occur with the orexin agonists. At this point, it looks as though it's something that gets better over time, and it doesn't look as though it's persistent. You have to recognize we're dealing with a research population which is really quite different from a clinical population, because clinical patients have a lot of comorbidities. We've heard quite a bit about depression today, and there's anxiety disorders, two of the most common comorbidities in narcolepsy, both of which can be associated with disturbed nocturnal sleep. There's a question about orexin agonists. I begin to see some worsening of that. However, I think orexin agonists will probably end up by coming to market and they will be very useful medications. As we have seen, I believe these patients with narcolepsy are particularly sensitive to medications. By far, the majority of patients with narcolepsy have been on multiple medications. They're always changing from one medication to another. When you consider it, like something like high blood pressure, where a physician may put a patient on a drug for high blood pressure and the patient stays on that, sort of stable, maybe adjusting the dose a bit for years, not narcolepsy. There's probably not a single narcolepsy patient out there who's just been given one drug and has stayed on that drug for years. It just doesn't happen. There's a lot of change. There's always a need for new medications and then a need for medications that have different mechanisms of action. As I mentioned earlier, we often combine different mechanisms of action together to try to get the best improvement in patients with narcolepsy. Having new medications that have been shown to be effective for the primary symptoms of cataplexy and excessive sleepiness is going to be very useful. Is every patient going to go onto this drug? Probably not, no. We've got other drugs that can be effective, but as I say, we've combined them and probably the majority of patients are on three or more medications for their narcolepsy. This gives us an alternative. There's always patients who have problems with the current treatments. As I showed you, that crescendo data, even with combinations of treatments in narcolepsy, a large percentage of patients still have symptoms. If we can use new medications in combination, it's going to make a big difference, I think, in managing these patients. I don't see, I mean, some people sort of think, oh, orexin agonist, they're going to be miraculous. Every other drug in narcolepsy is going to go away. It's not going to happen. Definitely not going to happen. These patients are so sensitive to medications and they all react very differently. There's always needs for new medications and new treatment directions. Thank you, Dr. Thorpy. Thank you for that presentation. Yatin Suneja from Guggenheim. Could you touch a little bit more on the cognition aspect? It seems like a lot of patients have that issue. What is your experience with current standard of care? How much impact do you see on? Cognition aspect, and then what is it about this mechanism that is probably driving some of the cognition impact or effect that we are seeing with this drug? Yeah, as I showed you there, a large percentage of patients even on current treatments are reporting that they still have cognitive impairment. We don't fully understand cognitive impairment, sort of being the last thing that we've really looked at when it comes to narcolepsy in terms of symptoms, primarily because we haven't really known the best way to get around handling it. As I mentioned, for years we've always thought that the cognitive impairment is just directly associated with the excessive daytime sleepiness. That doesn't seem to be the case. Even when patients improve in their sleepiness, there's still some cognitive impairment there. That's manifest by things that I mentioned. It's memory difficulties, concentration difficulties. Brain fog is an extremely common symptom in these patients. It's sort of hard for them to describe, and patients describe it in many different ways, but they just don't feel they're not sleepy. It's just that they can't see clearly or think clearly. This cognitive impairment is an important thing. I think we're only just starting to do studies, and this is one of the first studies that's really got to the stage of looking at cognitive impairment in patients with narcolepsy. Fortunately, we are seeing some improvement there. I think that's a very positive thing. Exactly what the mechanism of it is, I don't know. We talk about orexin as being primarily affecting REM sleep and sleepiness, but when you look at the pathways for orexin, they're very widely distributed through the brain. They go to virtually every part of the brain. If you're knocking out orexin cells, you're affecting a lot more than just the sleep-wake mechanisms or REM sleep. Whether it's some other effect of loss of orexins that's having a part, whether it's partially related to other factors, as I mentioned, there's some evidence that norepinephrine may be involved in a loss in narcolepsy. Maybe it's independent of the orexin, maybe it's something else that's causing it. I'm Mitchell Kapoor from H.C. Wainwright. Would like to get your thoughts on. The potential for a combination of reboxetine and solriamfetol mechanistically. Then separately, how competitive do you think reboxetine is likely to be in idiopathic hypersomnia? Okay, so combinations. Yeah, I see reboxetine being used a lot in combinations. There are clearly going to be some patients who, you know, I suspect this drug, when it becomes available, is going to be unscheduled and it's going to be very easy. I was discussing a little earlier with someone that, you know, one of the biggest problems we have as clinicians is dealing with insurance companies and medications. It seems to be getting more difficult as time goes on. Nearly every medication I prescribe we have to either get prior approval before we give it or we got to get prior approval six months after they are on it. At six month intervals, even patients that have been on the same medication for years, they get a six month prior approval and at the end of it, we've got to go through the whole process again. It's become really painful. Having an unscheduled drug that potentially could be prescribed for 12 months, I think has a lot of advantage and I think a lot of physicians are going to see that it's a big advantage of this. In terms of combinations with solriamfetol, I think it will be used in combination. I mean, initially, I would probably see it being combined with oxybates, which are extremely effective for narcolepsy. Oxybate plus reboxetine, to me, looks like a good combination. Patients that can't take oxybate, using it with another alerting agent, such as solriamfetol, probably. To my knowledge, we don't have any data on any interaction between those two, but that's something that obviously we would need to find out as we go forward. Assuming that there's no negative interaction between solriamfetol and reboxetine, there could be a good, good treatment combination, particularly in terms of the fact that we've seen here very robust effect on cataplexy. There's a good effect on daytime sleepiness. We know that daytime sleepiness is the hardest symptom to treat in narcolepsy. Nearly every patient, no matter what combination they're on, always still has some daytime sleepiness. Maybe adding a little solriamfetol in with reboxetine may be good in helping to relieve that. The other part of your question, last part. You had a second part? Yeah. Idiopathic hypersomnia. You know, idiopathic hypersomnia is a really difficult sort of condition. It's a heterogeneous condition, and that's one of the problems with it. We have those patients with idiopathic hypersomnia that look like patients with narcolepsy, except for they don't have the abnormal REM sleep phenomena. In fact, in many cases, you do the tests, they don't have the REM sleep phenomena. You repeat the test later, and they do have the REM sleep phenomena. You diagnose them with idiopathic hypersomnia, then you have to change it to narcolepsy. There is that group that looks like narcolepsy in normal nocturnal sleep, daytime sleepiness during the daytime. There are those that have long nocturnal sleep and they have difficulty in awakening, or what we call sleep inertia. Those patients, at the current time, the only drug that's FDA approved for the treatment of idiopathic hypersomnia is oxybate. Oxybate helps shorten the duration of nocturnal sleep, and it improves alertness upon awakening in the morning, as with all the other, including the orexin agonists. I didn't see a big role in those drugs in treating the long sleeper at night. There is a possibility, we've discussed maybe that we'll have some of these patients put on an alarm, wake up, you know, 4:00 or 5:00 A.M., take a medication, go back to sleep and then they'll wake up early. There are things like that that we can probably do, but in terms of daytime administration, it's not going to make a lot of difference to their duration and nocturnal sleep or their alertness upon awakening. I don't know that reboxetine would have any effect in those long sleepers particularly. Obviously it hasn't been studied in that group, the group that looks like narcolepsy, type 2 narcolepsy where sleepiness is a predominant, predominant effect. I could see reboxetine being useful in those and again being non-scheduled, able to prescribe for 12 months at a time, has a lot of positive effects associated with it. What I didn't show you here, but there is some data from the studies with regards to mood disorders and reboxetine and there is an effect and reboxetine was an antidepressant, you know, wasn't a great antidepressant, but it does have antidepressant properties and psychiatric disorders, anxiety disorders, depression, extremely common in patients with narcolepsy and so having some effect there. As I say, there was a little bit of data from the Symphony study showing some improvement in mood with reboxetine. That may be another plus. That is actually one of the areas that I'm particularly excited about because these patients with narcolepsy, so many of them have depressed mood and may not reach the diagnosis of major depression, but there's a depressive effect that's there. If this helps, in addition to its effect on sleepiness and cataplexy, helps improve that, that's a big plus. Super quick one for me. Miles Minter from William Blair. Some of the experts we talk to. In the space are sticklers for the maintenance of wakefulness test, and maybe that's because of the orexin 2 agonist data. I'm not sure where it's coming from. How important is that endpoint commercially speaking for AXS-12, or is this more. A drug that, you know, let's prescribe. It for cataplexy looks really good there. As you were pointing to, combination therapy can kind of take care of the rest on the EDSS side. Yeah, you know, maintenance of wakefulness test. This is, for those of you not familiar with it, it's a test where you measure someone's ability to remain awake during the daytime. It's a test that's commonly done in terms of looking at medications and looking at alertness. It's an objective test. Patients are put in a darkened room and try to remain awake. Usually if they can stay awake for more than 20 minutes, they're regarded as being sort of normal. The test can be either a 20-minute or a 40-minute test. Some of the tests with the newer medications, and you mentioned the maintenance of wakefulness test, have been studied in recent studies such as the orexin agonist, and it's shown robust effects on that objective test. At the end of the day, subjective measures are also extremely important. It's not just having an objective measure. I think the maintenance of wakefulness test is a useful test. I could see it being used for most studies. We don't have data on maintenance of wakefulness tests with reboxetine, but we have seen subjective data both in terms of clinical PGI as well as patient PGI data. Patients improving subjectively is an important endpoint. I wouldn't minimize the role of maintenance of wakefulness test. Okay, thank you very much. Thank you so much, Dr. Thorpy. It is now my pleasure to introduce. Dr. Andrea Chadwick to the stage. Will provide an overview of fibromyalgia and also of the previously completed Phase 2 and Phase 3 trials of AXS-14 in fibromyalgia. Thank you. Good afternoon, everybody. It's a pleasure to be here. Just as the other clinicians in the room, I can say wholeheartedly that anytime I can get in front of anyone and speak about fibromyalgia, I know that I'm doing a great service for my patients and all of the people across the world who suffer from this very common condition. All right, what is fibromyalgia? It is a chronic and debilitating neurological pain syndrome that results from dysfunction in central nervous system pain processing. There's an estimated 17 million people here in the United States who are impacted by fibromyalgia. What do these patients experience? They experience not only chronic widespread pain. This isn't localized pain just to the knee, as we see in knee osteoarthritis, or to the wrist with carpal tunnel syndrome. This is widespread pain and hypersensitivity even to innocuous touch outside of pain. Patients with fibromyalgia have disrupted sleep, usually shown by insomnia, fatigue, as we've been discussing with other conditions, mood disturbances such as depression and anxiety, and cognitive impairment. Interestingly, we're learning a lot more about this condition through the use of magnetic resonance imaging, et cetera. What we're also finding out is that this encompasses an overall global sensory hypersensitivity, where patients are also feeling almost as if sights, smells, and sounds are noxious. There's some really compelling data coming out of the University of Michigan showing that visual stimulation actually activates pain centers of the brain and peripheral with fibromyalgia. What we know about the impact on patients and society is that this is associated with substantial physical disabilities and really impacts their ability to function in their roles in their own lives. What does that mean? That means showing up to their places of employment and feeling their best to be a good employee. It means maybe not being able to show up for their families and their friends in ways that they wish to be doing. This is highly distressing because the majority of people who get this condition are young adults well up into menopause. These are the ages where we're living our best lives, either in our employment with our families and friends. There's a very great impact on this, not to mention the financial burden that this costs on society and on the health care system. I just want to point out this term, nociplastic pain. Those of us who study pain really look to the International Association for the Study of Pain to help us characterize different types of pain. Historically speaking, when I was a fellow at the University of California, Los Angeles back in 2009, we really only knew about nociceptive pain, which is pain that arises from inflammation or tissue damage, or neuropathic pain, which is a disease or lesion of either the peripheral or central nervous system, which could be exemplified by painful diabetic neuropathy or post-stroke pain. In 2016, the IASP introduced a new term, and this was the first time that this really legitimized the underlying pathophysiology that we see in fibromyalgia. I'm just going to read the definition here. It's pain that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors, or evidence for disease or lesion of the somatosensory system causing the pain. This formal third pain mechanism definition really allowed us to explain fibromyalgia and other conditions that exhibit this pathophysiology. As you can see here, there are listed some other very common pain conditions that affect persons worldwide, including irritable bowel syndrome, migraine, and tension headache. Even chronic low back pain is amongst what we call chronic overlapping pain conditions. They are recognized by the National Institutes of Health as having that same central sensitization pathophysiology that underlies their disease processes. Given the general historical path that we've had in fibromyalgia, back in the 1970s this was treated by rheumatologists. Actually, it was felt to be an inflammatory condition. It was called fibrositis. It was also called psychogenic rheumatism, kind of lending to that idea that it may have been an inflammatory condition or it very well may be a disease of a sad housewife. We've had this knowledge that has been building and building over time. What's really great is in 1990 they really legitimized that this was a chronic pain condition. It is not inflammatory and it is not dependent solely on psychiatric factors. In 1990, the American College of Rheumatology came out with the first set of accepted diagnostic criteria that did not change until 2011, where they switched from having a tender point exam to doing a self-report survey that again encompassed a lot of these other issues that patients with fibromyalgia deal with. We know it's not just tender spots on the body. This is an entirely different problem that encompasses the central nervous system that we can't just gauge by pressing on a patient. Because of this, because there are all of these different symptoms going on just as we've talked in other conditions, this is very heterogeneous in how it presents. Barriers to diagnosis really have been limiting access to not only timely care, but timely diagnosis. As you can see here, about six years from their initial presentation to symptoms is when a person presenting gets their actual diagnosis of fibromyalgia. Within those six years, they are seeing at least on average about four physicians or clinicians to try and get that diagnosis. These people are ending up in general practitioners' offices, they're ending up in gastroenterology clinics, they're ending up in neurology clinics, they're ending up in rheumatology clinics. It takes a very long time for them to get that diagnosis. Again, I think not only because of this historical transition towards different types of diagnostic criteria, but I really would like to point out, as many of the other clinicians on the panel have said today, a lot of these conditions have a very high stigma. When you guys heard that you're going to be hearing about fibromyalgia today, are any of you aware of the condition? Yeah. Does anybody have family members with the condition? These patients are highly stigmatized. I would say not only just in society, but also in clinicians' offices. I have seen notes from other providers, from patients of mine, where there's a note that says they don't look like they're in as much pain as they're saying they're in. These patients are marginalized, they are dismissed. Ultimately, the legitimization, I think over the last couple of decades, has really led to us being able to get excited about treating fibromyalgia. I know I show up every single day and feel very good about seeing these patients. Let's talk about the impact on people's lives. You know, imagine a person who's being told that it's all in their head or that if they would just exercise and get happy that they would feel better. That really makes it difficult for patients to feel like they can show up as their best selves and feel empowered to have a good life. The impact, I think a lot of other clinicians in the room have really talked about how many of these neurological conditions impact people's lives. We know that there's lost days at work due to their symptoms. They have a reduced quality of life. They're not interacting with their peers and their friends and family as much as they'd like to. They have a greater overall health status impairment versus other chronic pain conditions, just as we've heard with some of the other conditions. A high rate of comorbid psychiatric and medical conditions. We see a lot of depression and anxiety in our fibromyalgia population. High health care utilizers, as I mentioned, these patients are seeing an average of four clinicians before they're able to get their diagnosis. They do have a higher rate of polypharmacy. Again, because there's really no true medical home for fibromyalgia. If you think about diabetes, they're seeing endocrinologists. If you think about heart failure patients, they may be seeing cardiologists to manage these conditions. There's no one specialty that's really taking ownership. They're kind of ping ponging around to different clinicians trying to get help. Ultimately, that ends up with one provider putting them on this drug, another provider putting them on that drug. These patients are very challenging and complex, which is why I think overall they've kind of been put to the wayside when it comes to not only the research in this condition, but empowering clinicians and educating clinicians on how to treat it. Just a little bit of some voices from patients and I want to highlight the two most important symptoms that patients with fibromyalgia have and that's that chronic widespread pain, but fatigue. We've heard a lot about fatigue today and this is the type of fatigue where they may sleep, but they wake up feeling unrefreshed and they are dragging through their days. Here's a quote from a patient saying, I literally hit a brick wall. All of a sudden I come to a complete and total stop with regards to their pain. The pain is so bad it feels like there are knives sticking into my body. These are really, really impactful statements to show again that these patients, they're worrying about their future. Are they able to remain employed? Are they going to make it to their son's graduation ceremony because they're dealing with such debilitating symptoms? I'd like to talk a little bit about key challenges, and I had a chance to speak to some of the gentlemen over here at my table. I was historically and classically trained to be an interventionalist. Most of the people in my space are doing injections to make people feel better, looking at neuromodulation, spinal cord stimulation. There's been this huge boom in treating other types of chronic pain when it comes to fibromyalgia. We've only had three FDA approved products for fibromyalgia with no new therapies or innovations within the last 15 years. I have patients who show up to my office and they're like, anything new yet? I have had to continually tell them no, which is why I'm so excited to talk to you today and to learn that there are these new products being developed because patients, and I would say clinicians, are very desperate for it when it comes to managing this condition. It's very important to point out that there's no one drug or monotherapy that typically gets these patients to where they need to be in terms of pain reduction, symptom improvement, and functioning. It requires multidisciplinary care, very patient focused on what their goals and expectations are. In addition to pharmacologic therapies, we also look at some non-pharmacologic interventions. We do know that activity, cognitive behavioral therapy, and other types of potentially even complementary and alternative medicine avenues can be explored to improve the symptoms related to fibromyalgia. Now, what do we use? What are we using currently out in practice? I would say historically we've been using serotonin norepinephrine reuptake inhibitors, very rarely just selective serotonergic agents. We can use skeletal muscle relaxants to treat some of those peripheral muscle pains or spasms that they may be dealing with. I will say I trained in a very opioid heavy time, and opioids are very much kind of a hot box topic. I'm not going to really go into it because that's not the focus of today. You would be surprised to know that in the top five agents used for treating fibromyalgia, opioids are still in the top five, even though we know that they are not helpful in treating the condition. In fact, for some people with fibromyalgia, opioids can actually make their pain worse because of how opioids can affect the central nervous system. In terms of the FDA approved medications, those account for less than a third of what we recommend for patients. We use a lot of off-label therapies to treat these patients, mainly because of the high rates of patient dissatisfaction with what's currently available, whether it's due to inadequate symptom control or tolerability issues. As was discussed with narcolepsy, a lot of these patients that are coming into my office are on a rotation of different medications because they're trying to find that right magic formula for helping them get better. Interestingly, more than 50% of fibromyalgia patients discontinue treatment within the first year. Many of them just give up on therapy and go about their days trying to manage it the best they can by themselves. Let's talk about AXS-14, which is S-reboxetine. It's a more potent and selective enantiomer of the racemic reboxetine. What that does is it inhibits the reuptake of norepinephrine, leading to increased norepinephrine activity and ultimately decreased pain signaling. Why is that important? What we know in functional MRI studies of patients with fibromyalgia and other types of nociplastic pain conditions is that when we do a painful stimulus or even look at rest in patients with these conditions in a functional MRI, we actually see decreased connectivity to areas of the brain like the periaqueductal gray and the rostroventromedial medulla. Those areas of the brain are very important when it comes to descending pain inhibition. Our brain has this really uncanny, cool ability to either facilitate pain or inhibit pain. In our patients with fibromyalgia, they have that impaired inhibition, so they're shunted towards that facilitatory pain signaling. That's what leads to that hyperalgesia and allodynia that we see in these patients. Ultimately, this makes norepinephrine a really nice target for trying to optimize the availability of the neurotransmitter that we know will help improve descending pain inhibition. There have been two studies performed in AXS-14. There was a Phase 2 study in 267 patients. There was also a Phase 3 study in a little over 300 patients looking at the efficacy and safety of AXS-14 versus placebo in patients with fibromyalgia. The Phase 2 study, both of these were randomized and double-blinded as well as placebo-controlled. Phase 2 was 8 weeks and a flexible dose, meaning patients entered at 2 mg and then were allowed to increase after every 2 weeks by 2 mg up to a total dose of 8 mg. In the Phase 3 study, they were fixed dose and participants were randomized to either placebo, 4, 8, or 10 mg and followed for 12 weeks. In Phase 2, the primary endpoints were weekly mean pain scores. Those are our visual numerical pain score ratings, where 0 equals no pain and 10 is typically mentioned as the worst pain imaginable. The FIQ total scores, that's the Fibromyalgia Impact Questionnaire, which essentially tries to ascertain how severe is the symptomatology the patient with fibromyalgia is experiencing and how much is it impacting their functioning. The PGIC, we've heard a lot today as well. When we go over to Phase 3, we have many of those same endpoints, but they also included something which I think is very important, the modified GFI, which is the Global Fatigue Index. Having that additional endpoint, knowing that the FDA Voice of the Patient said that the two symptoms they care about most are pain and fatigue. Similarly to what we've looked at, lots of graphs today, but really wonderful to see here that there are significant reductions in weekly mean pain scores compared to placebo at week 14. This first column here is 4 mg, the second column here is 8 mg, and the third column there is 10 mg. Interestingly, you can see there is somewhat of a ceiling effect by the 10 mg dose. We are seeing less reductions in pain, but we still met all of our endpoints for all three doses. When it comes to improved patient functioning over time, looking at the well-being of the patients, how well they're able to physically function and mentally function in their everyday life, we again see significant reduction in patient functioning and well-being as measured by that Fibromyalgia Impact Questionnaire total score compared to placebo at week 14. That carried on for all of the doses. Fatigue. We have talked about how this is the second most important thing that patients with fibromyalgia care about. We again see reductions in fatigue as measured by that global Fatigue Index score compared to placebo at week 14. Just a little bit on Phase 2 here and then we'll wrap it up. I'm hoping that there will be a nice robust discussion after this. The Phase 2 results here demonstrate rapid reductions in fibromyalgia pain when compared at eight weeks compared to the baseline. Again, just as some of the other clinicians in the room have mentioned, I also view these very rare rapid improvements as being a very big selling point because these are patients who are literally trying to get through their days. They end up in my offices, they are desperate to get their lives back. If we can get improvement by week three, that is a huge, huge selling point for us as clinicians because many of the other FDA approved agents or other off-label agents that I use sometimes take months if not like a half year to try and really get that true testament of whether or not it's going to be helpful looking at patient functioning. Same thing here, significant improvements in patient functioning and well-being as measured by the FIQR total score. Same thing, reduced fatigue. I was really excited to see this data just as a lot of the other clinicians. I'm a clinician scientist, I really enjoy spending my time understanding mechanisms, looking at mechanistically based treatments. I still see patients in clinic. In fact, I'm flying back tonight and I'll be seeing patients tomorrow. The one thing we care about in the clinic is how can I get these patients better, what tools do I have in my toolbox? I have not had a new tool in 15 years. If I can get a new tool, and I know a lot of other clinicians out there who treat fibromyalgia, if they can have another tool in their toolbox to help these patients who are suffering, I think we all should get excited about that. Some key takeaways and then I'll take some questions if there are any. Fibromyalgia is a very significant and common debilitating neurological pain syndrome affecting the central nervous system. About 17 million people in the United States. Broad range of symptoms that impacts every facet of their life. We know that existing treatments provide inadequate symptom control due to tolerability issues. AXS-14 really represents that novel pharmacologic approach for the management of fibromyalgia. I really think it fills a lot of gaps in care, which I can outline a little bit more through questioning. It does play a really big role compared to what we currently have. Thank you. Thank you. David Amsalem from Piper Sandler. I have an S-reboxetine specific question. Just knowing what we know about its mechanism, it's noradrenergic. We've got a couple of those that are noradrenergic that are approved. On one hand, it's clear from your commentary that there's a need for another, as you point out, tool in the toolkit. What specifically does S-reboxetine bring to the table that can provide more improvement, more clinical benefit for patients compared to what we're seeing now? That's a really great question. I'm glad you asked that. Where I was hoping to go with providing some additional flavor on this is with our noradrenergic agents. Duloxetine and milnacipran, the issue is they still have serotonergic activity. It makes it very difficult for me to prescribe duloxetine or milnacipran in patients who are taking concomitant SSRI or other types of serotonergic agents. That for me is one of the biggest selling points. Additionally, we don't know from these studies that have been done, but with our SNRIs and SSRIs, having those sexual dysfunction side effects has been very disturbing to patients. If there's the potential that a noradrenergic agent only would not cause those side effects, as we know are typically related to the serotonergic component, I for one see that in a group of people who are really in the prime of their lives as being a very positive thing as well. Hi there. Thank you for the presentation. Jothurm, from TD Cowen. You indicated that it does take several physicians and years to make the diagnosis. Is there a common last stop? At all, whether it's a pain neurologist or PCP, after years of working with. The patient and maybe if you were. Axsome, what's the right kind of physician touch point to maybe change this paradigm a little bit? That's a great question. I would say typically speaking, your sub-sub specialists, people who are like anesthesia pain management or neurology pain management, are typically where these patients end up at kind of an end of the road. If you are one of the unicorns out there who takes this on and enjoys treating it, there are rheumatologists that I know of who do this, etc. I really think the catchment that we should be focusing on is primary care. Diagnosing this condition is through a self-report survey that takes about five minutes tops for patients to fill out. Historically, this has been thought to be a diagnosis of exclusion, meaning you have to do the pan scans, all the lab work, all of this very expensive workup through specialists to try and say with certainty this is fibromyalgia. What we know about the current accepted diagnostic criteria that was revised in 2016 is that you do not have to exclude everything else to say with certainty that fibromyalgia is a diagnosis. It doesn't mean you still shouldn't work it up, but that allows for that moment to say, how are we going to address this? We'll look at this other stuff too. For me, the primary care clinics are really where the education needs to be. Overall, do I believe primary care can manage this condition? Absolutely. Hi, I'm Ifadia from Needham. Can you talk about whether there are. Specific types of patients where this is most appropriate for, or should we think about the market differently, where just patients are just not achieving their goal. They're cycling through treatments. With building awareness, you're. Going to be able to kind of get utilization of the drug? I mean, I view this as a first line agent mainly because of its tolerability, its side effect profiles. One of our FDA approved agents is pregabalin, which is a calcium channel blocker. It's also scheduled. We've heard a lot about what the impact of scheduled medications have for clinicians and patients alike. For me, with pregabalin, that's not typically a first line agent for me, even though it is FDA approved, mainly due to the potential for pretty disturbing side effects in patients. It can cause significant weight gain. I'm not talking about a couple pounds. I've had patients gain 20 to 30 pounds within a month or two. That's very distressing for them. It also causes a lot of somnolence and it worsens their cognitive slowing, typically speaking. To have a drug that's not going to cause more symptoms of what they're already experiencing, I view AXS-14 as being more of a first line agent that could be offered to anyone within a primary care clinic or a specialty clinic as well. Dr. Chadwick, thank you so much for that presentation. Yatin Suneja from Guggenheim. Could you talk a little bit about the dosing? It seems like there is a plateauing. Of an effect that you just mentioned. You know, the other concept. I want you to touch on in this flag, flexible dosing versus fixed dosing. The reason I ask you that question is because the FDA has asked the company to run another study with a fixed dosing. I'm just curious to understand these. Concepts, how relevant they are. What do we learn from flexible or versus fixed? Thank you for your question. Typically speaking, with our current FDA-approved agents, we do definitely start with a flexible dosing paradigm. I think that very closely mimics clinical practice. Everybody's hepatic enzyme activity of their livers is different, and some people respond very, very well to low doses of these types of compounds, and some people need higher doses. I will say with regards to how we kind of saw that ceiling effect at 8 milligrams and how the 10 milligrams had less impact, we see this in duloxetine. With duloxetine, you've got zero, you've got 20 milligrams, 30, and 60. Typically speaking, for fibromyalgia, it's FDA-approved up to 60 milligrams. When we look at doses higher than that, we typically get that ceiling effect. This would be increasing to 90 or 120 with duloxetine. I think that's a little bit of what we're dealing with here when it comes to the issues surrounding the FDA. I was going to hope that perhaps Axsome Therapeutics might be able to speak to that. Sure. The feedback we received from the FDA, and this is through the NDA submission process, is that they wanted a second Phase 3 trial with fixed dose because. That's their preferred paradigm. For pain indications. Or at least that's the Pain Division's. Preferred approach for registration, trial design. Yes. I would just like to throw kind of my expert knowledge about the studies that have been previously done. They were done before we had new diagnostic criteria for fibromyalgia. When you look at the two studies that I've presented here, they were in terms of their inclusion criteria, criteria using the old 1990 diagnostic criteria, which has again fallen out of favor in terms of diagnosis and actually has been reported to underdiagnose the condition. I imagine that in these future Phase 3 studies, using the new dogma of diagnosis will likely improve the rigor of the studies that are performed. Thank you so much. It's been a pleasure. Thank you, Dr. Chadwick, for your insights. Perspectives on fibromyalgia. Our final guest speaker today is Dr. Stuart Tepper. He'll be providing an overview of Symbravo. In migraine and a review of. The Phase 3 clinical trial data. Thank you. Every single person today has talked about their particular disease and pointed out the same features, high prevalence and unmet need. Everybody, I will say migraine is the most prevalent. 40 million. 40 million. We're the worst. It is, according to the World Health Organization, tied with major depressive disorder for years lived with disability. This is very serious in terms of the disability, not that all the other disorders were not. They are. They have features that are similar in that patients have repeated times of disability that really knock them out. This is true in migraine. There is an International Classification of Headache Disorders that's been adopted by the FDA and the World Health Organization. Briefly, migraine attacks are characterized by generally severe, often unilateral headache, pain interfering with activities and associated with nausea and with photophobia and phonophobia, that is, sensitivity to light and noise. People can't work with that and it disrupts their lives, very similarly to what you're hearing over and over again today. Similar to what has been described today, there's high patient dissatisfaction with existing treatments. I was thinking about Ari Maizel's very initial presentation that Axsome Therapeutics was going to look at diseases where there's a high unmet need and where there's patient dissatisfaction with treatment. Migraine, again, along with everything else you've heard today, is similar to that. Within the last couple of years, in several studies, over 80% of patients discontinued their as-needed treatment, the treatment to terminate migraine, their acute treatment, and 75% of the patients felt that their oral acute medicines were suboptimal in some way. It might have been efficacy, consistency, tolerability, side effects, the same kinds of things you've been hearing about all day. Let me take my shot at describing what migraine is. Again, a neurologic disorder. We know from functional imaging that even before pain, two or three days before pain, there are functional changes in the brain that go from the hypothalamus to the upper brain stem to the lower brainstem. These are stereotypical changes that turn on in the brain. Patients experience a prodrome and then the brain sends out a pathway to the meninges. In the meninges there is the release for most patients of calcitonin gene-related peptide, which is CGRP, the infamous CGRP. The CGRP lands on a docking station and causes blood vessels to dilate and is associated with the activation of prostaglandins and neurogenic inflammation. What happens in the meninges in migraine is that for each attack, people are getting blood vessel dilation and inflammation. Every attack, and I tell this to patients, every attack of migraine is meningitis. It's not infectious meningitis, but it's meningitis, which is why it is so severe. The pain signal then goes back into the brain and it's processed. When one thinks about how to terminate that, part of the idea is to terminate it by attacking CGRP, which you can see here in the time course of the migraine peaks within an hour. Part of us thinks maybe we should be concentrating on the prostaglandins and the inflammation, which you see here peak in the first hour to two hours. The CGRP levels come down pretty fast, but the inflammation, the prostaglandin-induced inflammation, persists and that leads to the length of the migraine attack, which by international criteria is up to 72 hours. In certain circumstances, such as menstrual migraine, which occurs in 2/3 of women with migraine, the migraine can last longer than 72 hours and be more severe. Our acute treatments have kind of carved out individual approaches to try to terminate migraine. Most of the most used acute treatments target CGRP in one way or another. Ergots and triptans and lasmiditan prevent the release of CGRP, and ergots and triptans constrict the blood vessels that CGRP dilates. Gepants are a new drug before Symbravo; gepants block the CGRP receptor. Each of those kinds of acute treatments target CGRP and not the inflammation. Nonsteroidal anti-inflammatories are attractive because they target the inflammation peripherally; they terminate inflammation everywhere. That's why we use them in arthritis, for example. Nonsteroidals also work inside the brain. What happens in the migraine pain mechanisms is after the meninges is activated, the signal goes back into the brain and it's integrated. That's when people get sensitivity to light and noise and nausea. That's called central sensitization. Triptans don't work that well on central sensitization, but nonsteroidals do. What we're trying to do for the acute treatment is to give patients flexibility so that they can treat early and terminate an attack without side effects, or if they miss the window, treat late and be able to terminate the migraine without side effects. One of the nonsteroidals that has been of interest from a clinical standpoint is meloxicam. The problem with meloxicam, which has a really nice long activity and might prevent a headache from coming back or work on a very long migraine, is that it's very generic. Meloxicam, or Mobic, is very slow in onset, takes four or five hours to peak. That's not going to be useful in stopping a migraine. For that reason, there was the development of a new formulation of meloxicam. This is meloxicam in little tiny carrier molecules. These carrier molecules, which I won't go into great detail in, get the meloxicam in more rapidly and allow the possibility of using mosaic meloxicam, as it's called, to terminate migraine. One could have, on the one hand, the meloxicam to work on the inflammation peripherally, but also centrally. On the other hand, if you added a triptan, and the fastest oral triptan is rizatriptan, you might have a combination with multiple mechanisms that would give the patient the flexibility early and late and work well. The question is, what would the pharmacokinetics look like? The answer was the pharmacokinetics were very fortuitous. It looked like the two components helped each other so that the rizatriptan, which you see here in blue, the time to maximal serum concentration and the maximal serum concentration were all improved. Earlier onset, higher levels, and the meloxicam you can see peaked, it's in green, peaked at the same point as the rizatriptan. Both of them at an hour or before, they would peak before the CGRP peaks, before the prostaglandins peak. You can see, remember the CGRP comes down, but the prostaglandins are maintained. You could get this combination of benefit with this combination medication, Symbravo. Of course, one of the big questions is do you pay a therapeutic penalty when you do that? Do you get more side effects? I'll show you at the end. The very unusual aspect of this is you get less side effects. There were three large studies that I'd like to present, two regulatory trials. The first called Intercept, the second called Momentum. The way to remember them, which Ari Maizel told me to use, which I have used ever since, is that the Intercept study was done in, and patients were told to treat with the Symbravo early in the attack when the pain was mild. That's what we do clinically, we tell the patient use it early. Your patients are trying to intercept the migraine. In the second study, which was an FDA regulatory trial where there was some imposition of requirements by the FDA, patients were told to wait until they had moderate to severe levels of pain to treat. It was a modified factorial study so that you had meloxicam mosaic, meloxicam as one group, rizatriptan as a second group, combination Symbravo as a third group, and placebo. In that study, the Momentum study, Axsome did something else that was a little daring. They selected patients that had had poor acute treatment efficacy in the past. They actually selected patients that were more difficult to treat for the Momentum study, and finally, the Emerge study is an open-label study of patients for whom the gepants had failed in one way or another. Here are the efficacy results in the first two Phase 3 trials. Now remember, the Intercept study is what you would see clinically, is what we see clinically. In that, and what the FDA mandates, is that the drug has to meet two co-primary endpoints. Patients have to be pain free at 2 hours, not relief, but completely pain free at 2 hours compared to placebo. Patients are instructed to choose their most bothersome symptom from either sensitivity to light, sensitivity to noise, or nausea at the beginning of the attack. They have to be clear of that most bothersome symptom at 2 hours. Both of those co-primary endpoints have to be positive to get regulatory approval. As you can anticipate, if a patient treats early, the likelihood of pain freedom at 2 hours is going to be a lot higher. A third of the patients were pain free at 2 hours in the Intercept study. In the Momentum study, it was about 20%. Most bothersome symptom freedom was also positive against placebo for both of the regulatory trials' response. When most bothersome symptom freedom was first promulgated, it turned out that placebo response in MBS freedom is always a bit higher than for pain freedom. Remember that we're interested in the acute effect, quick, that is within those 2 hours, but we're also interested in the sustained effect, that is, is the meloxicam doing both of the tasks that we set forth for it. I was an investigator on these, and that is, we wanted to get the pain freedom at 2 hours, but we also wanted sustained pain freedom and the headache not to come back. Sustained pain freedom has a very precise definition. It's pain free at 2 hours without use of rescue medicine over the next fill in the blank. If it's 24 hours, it would be 22 hours, or 48 hours, and no use of the study drug or the active drug over that period of time. For both of the studies, the sustained pain free response was superior to placebo. In the modified factorial studies, depending on the endpoint, the Symbravo always worked numerically or statistically better than the individual components. That translates, because it's part of the definition, into reduced rescue medicine over that 2 to 24 hour pain period. For example, in the Intercept study, 40% of patients needed rescue medicines after the achieving of the pain free response, 15% with Symbravo. Similarly, in the Momentum study, looking at the modified factorial, the Symbravo was numerically or statistically better than the individual components or the placebo. It looked like it was doing what we wanted it to do. Now, I want to show you some other ways of evaluating whether the Symbravo is working the way we want it to work. The first subgroup analysis that we wanted to study was menstrual migraine. Menstrual migraine, as I said, occurs in 2/3 of women with migraine and close to 20% of women in the general population have migraine. This is a huge number of patients. Menstrual migraine is clearly longer than non-menstrual migraine and more difficult to treat than non-menstrual migraine. Every headache specialist will tell you this. What we wanted to see was that first of all the efficacy at two hours for the Symbravo would be adequate for menstrual migraine because that's the tough one. You can see 28% of patients in the Intercept study taking it early were pain free at two hours. The MBS, the most bothersome symptom, was also eliminated at the two hours. This is very hopeful for us because it suggests that the meloxicam persistence of effect is going to help with menstrual migraine, but also the two hour quick onset is going to be present. Another area where we were interested is in morning migraine. This is not a well known fact, but in multiple circadian studies of large numbers of attacks, like 3,000 attacks in the study by Tony Fox, 50% of the migraine attacks were in the morning, between 5:00 and 9:00 A.M. If a person wakes up with a migraine they are usually already centrally sensitized. The migraine began while they were asleep, it progressed, they awakened with the attack, it's already moderate to severe, they've already got, fill in the blank, sensitivity to light, sensitivity to noise, nausea, allodynia. That's very difficult to treat. Oral triptans don't generally alone bring the patient back from the dead once they awaken with an attack. Getting to work with a morning migraine, having something that is reliable for morning migraine is quite difficult because whatever you use has to reverse central sensitization. The brain is turned on, it activated the meningeal pain mechanisms and then the signal has gone back into the brain and it's processed and that's when the patient wakes up. It turns out that nonsteroidals are one way to reverse late in the attack. The hope was that the meloxicam portion of the Symbravo would reverse that. Indeed, you can see in this morning migraine subgroup analysis in both of the groups, both moderate to severe and treat early, the pain freedom at two hours was comparable to that of the pivotal trial taking all comers. That is extremely hopeful for us. What I teach my fellows and my residents is ask the patient when their attacks occur. If they say sometimes in the morning and sometimes in the afternoon, you say what % occur in the morning? When you hear a significant % occurring in the morning, which is common, then suddenly this combination medicine becomes very attractive for treatment. One of the big questions of course is if you raise the rizatriptan level and you get the meloxicam in really early, will the patient have a lot more side effects? It turns out no. We don't know why everybody is asking this question in neurology and headache medicine. We don't know why there is not a therapeutic penalty for raising and speeding up the rizatriptan and getting the meloxicam in so early. In the pivotal trials, looking at the % of adverse events over placebo, somnolence was 1% over placebo, dizziness was 1% over placebo. This is an extremely, extremely well tolerated medication. As I say, we don't really know why, but some interaction between the components results in reduced adverse events and the adverse events lower than the individual components. There were no discontinuations due to adverse events in the studies. The way I teach that is to say you get this increased benefit both acutely and in terms of the length when you're intervening in the migraine, but you don't pay a therapeutic penalty in terms of side effects. Now the medication has also been studied in the Emerge study in terms of evaluating how it does in people who didn't respond very well to gepants. These are data on that showing that for two hour pain freedom and sustained pain freedom and what I care about, which is ability to return to normal activity, because that's the main reason we're using the acute treatment and ability to plan daily activities. For all of these, the Symbravo worked very, very well. These were, as I say, in people for whom the gepants had not worked well, had not been optimal. The way these patients were selected was to use a patient reported outcome measure we've heard about, PROs, already called the Migraine Treatment Optimization Questionnaire, which evaluated how well the previous acute treatment, in this case gepants, worked on all of those outcome measures. This was also an extremely helpful study to me because it tells me where I can use it even in people who have had a lack of success with previous treatments. The second pivotal trial took people who had had a lack of success with previous treatments. Over a quarter of them had had triptans fail. This study showing patients for whom gepants had failed. It's very, very hopeful for us. There's a lot of excitement in headache medicine about this. The idea for this combination medication really derived from understanding the pathophysiology of migraine. The clinical trials were actually propelled by the high patient dissatisfaction and the obvious need for better tolerated and more effective medications, and the new formulation of the mosaic meloxicam in combination with the rizatriptan resulted in very quick onset and durable effectiveness. Now we're beginning to see how it works in the subtypes such as long duration migraine, menstrual migraine, which is also more severe, or morning migraine where the patients are already centrally sensitized. I hope that woke you up. Oops. Am I supposed to leave this for you, Ari, is that. I'll back it up one and take questions. Hi there. Thank you for the presentation. Jotham from TD Cowen. Sorry if you missed this. What proportion of your patients do have that morning migraine and maybe would be the particularly excellent candidates for Symbravo. Just broadly as this therapy is launching, how difficult do you expect the reimbursement dynamic to be initially and maybe how many? What portion of your patients already clear that hurdle? I guess to be a candidate. It's awfully early on the second question. When I prescribe it, I give them the coupon, I give them some samples. Fingers crossed. That's more for the people that are trying to get it accessible commercially. What I said was that in two very large circadian studies, one was the entire Glaxo database of 3,000 attacks, morning migraine occurred in 50% of the attacks. It is extremely common. What I think happens most of the time with the older acute medicines is that patients either it doesn't work or they get relief but not pain free. If they get relief but not pain free, that's linked to the headache recurring and for them having to repeat doses. It also doesn't make people real happy. Sometimes what happens with triptans is that the patient will say, yes, I get pain free. I ask, but can you use the triptan when you need it? They say no, no, no, I have to wait till I'm back from work to take it because of the side effects. What percentage of morning migraine will I be using this in? It's going to be high. I did already prescribe it for somebody who was getting frequent recurrence with her acute medicines earlier this week. Whether it's every single patient with morning migraine, I don't know. It's going to be a useful addition to our armamentarium for morning migraine, that's for sure. What we have is inadequate. Thank you, Doctor, really appreciate your perspective. Matt Hershenhorn from Oppenheimer. Our questions are just maybe imagining from a reimbursement perspective, considering patients that discontinue other meds, primarily triptans, due to tolerability reasons, do you think that could confer better reimbursement? Also, people preferring Symbravo. Also curious if you have any idea on average how many migraine days per month your typical patient might have, and as a corollary, what severity level they might have if they're addressable with Symbravo. There are so many questions I can't follow them all. I suspect that the insurers are going to require step edits before they allow Symbravo to be covered. That'll probably mean two triptans before, two generic triptans before, one before they cover it. What we can say about a failure of triptans for particular patients is that between 25%, between a quarter and a third of the patients in the Momentum study actually had had a failure of triptans, and yet it worked. We know already that patients who had had a failure of triptan monotherapy are likely to be acceptable candidates for Symbravo and that the side effects, if the problem with the triptans was triptan sensations, the likelihood that they're going to experience that with Symbravo is very, very low. 1% over placebo and nobody with the chest and neck tightness that comes, for example, with sumatriptan so commonly. I think we have plenty of legs to stand on in terms of the step edits in getting there. Beyond that, how well it'll be covered and how difficult, that's way out of my area. I don't think the fact that we have all of these data in any way influences insurance companies in terms of coverage. I don't think they care. Thank you. Yeah, and by the way, while we're talking about prior approvals, which came up earlier, I don't know if you saw in The New York Times this week the study that looked through the Komodo database of what the percentages were of turning down submissions for PAs a decade ago versus now, but it's almost double. It's bad and getting worse, as one of the doctors earlier said. Hi, David Huang with Deutsche Bank. I had two questions. I believe there is a combo triptan and NSAID product out on the market. I think it's sumatriptan and naproxen. am just wondering your experience with that. Product and how Symbravo might stack up against it. Just in terms of labeling, how valuable would a preventative or prophylactic. Label be in addition to abortive treatment? Let me answer the first one. The previous combination, sumatriptan naproxen sodium pill, was excellent. GSK had included a new formulation of sumatriptan within that product. That led to a quick, quick onset of the sumatriptan. Once it went generic, that RT sumatriptan formulation is gone, and the generic sumatriptan naproxen combination doesn't work nearly as well. It's also extremely difficult to get. The second is that rizatriptan is not for prevention and alone. Rizatriptan at 10 days of use per month is associated with increased frequency of migraine and headache days, what's called medication overuse headache. Nonsteroidals used less than five days per month are associated with protection against medication overuse headache. In any case, this combination will not be used for prevention. I remember your other question. Your other question was how many attacks per month does the average person get? This lets me say bad things about the FDA. It's kind of a pile on according to The New York Times, from what I read on Sunday. What the FDA has done since the triptan era is to look at the safety extension trials for a particular acute medicine and take the median and say, okay, the safety of treating more than that number of attacks has not been proven, which is completely nonsense. I mean, it's nuts. Yet they keep doing it. In the prescribing information for Symbravo, it says the safety of treating more than seven attacks in a month has not been proven. However, I will point out there are nine tablets in the bottle. Yeah. David Amsalem from Piper Sandler. Just a quick hypothetical. In a perfect world where payer access insurance is less of a consideration or not a consideration, with these different classes of drug for acute treatment, the ditans, the gepants, triptans, you have Symbravo sort of straddling different mechanisms. Where would Symbravo fit in your practice? Probably fairly early. I think we would use gepants and Symbravo early because of the improved tolerability, the fact that they can be used early in attacks. In the case of Symbravo, because it's flexible, early and late for patients and without side effects. Gepants and Symbravo both have really excellent tolerability. However, I believe that the insurance companies will stop obstructing when there's peace in the Middle East. Are we done? Okay. Thank you very much. And on that note. Thank you very much, Dr. Tepper. That wraps up our presentations for today. Please join me in welcoming Ari Maizel back. To the stage for some closing remarks. Thank you all for joining us for today's R&D day. I would like to especially thank our physician experts, Drs. Chadwick, Cummings, Cutler, McElroy, Tepper, and Thorpy. With our growing portfolio of differentiated on. Market medicines and our pipeline of transformative. Investigational medicines, we are well positioned to. Advance clinical practice in brain health too. Improve the lives of the millions. Patients who are living with neuropsychiatric conditions. We look forward to keeping you updated. On our progress, and thank you all for coming. Have a great day.

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